Genome of the Asian longhorned beetle, Anoplophora glabripennis), a globally significant invasive species, reveals key functional and evolutionary innovations at the beetle-plant interface

USDA-ARS?s Scientific Manuscript database

The Asian longhorned beetle (Anoplophora glabripennis; AGLAB) is a globally significant invasive species capable of inflicting severe feeding damage on many important orchard, ornamental and forest trees. Genome sequencing, annotation, gene expression assays, and functional and comparative genomic s...

TURKEY FECAL MICROBIAL COMMUNITY STRUCTURE AND ECOLOGICAL FUNCTIONS REVEALED BY 16S RDNA AND METAGENOME SEQUENCES

EPA Science Inventory

Turkey feces are an important source of fecal waste in the United States. With the exception of isolated studies on bacterial pathogens, little is known about the type of bacteria inhabiting the turkey gut. In order to understand the microbial diversity and functional genes assoc...

Alterations in the coupling functions between cortical and cardio-respiratory oscillations due to anaesthesia with propofol and sevoflurane

NASA Astrophysics Data System (ADS)

Stankovski, Tomislav; Petkoski, Spase; Raeder, Johan; Smith, Andrew F.; McClintock, Peter V. E.; Stefanovska, Aneta

2016-05-01

The precise mechanisms underlying general anaesthesia pose important and still open questions. To address them, we have studied anaesthesia induced by the widely used (intravenous) propofol and (inhalational) sevoflurane anaesthetics, computing cross-frequency coupling functions between neuronal, cardiac and respiratory oscillations in order to determine their mutual interactions. The phase domain coupling function reveals the form of the function defining the mechanism of an interaction, as well as its coupling strength. Using a method based on dynamical Bayesian inference, we have thus identified and analysed the coupling functions for six relationships. By quantitative assessment of the forms and strengths of the couplings, we have revealed how these relationships are altered by anaesthesia, also showing that some of them are differently affected by propofol and sevoflurane. These findings, together with the novel coupling function analysis, offer a new direction in the assessment of general anaesthesia and neurophysiological interactions, in general.

Single-cell-type Proteomics: Toward a Holistic Understanding of Plant Function*

PubMed Central

Dai, Shaojun; Chen, Sixue

2012-01-01

Multicellular organisms such as plants contain different types of cells with specialized functions. Analyzing the protein characteristics of each type of cell will not only reveal specific cell functions, but also enhance understanding of how an organism works. Most plant proteomics studies have focused on using tissues and organs containing a mixture of different cells. Recent single-cell-type proteomics efforts on pollen grains, guard cells, mesophyll cells, root hairs, and trichomes have shown utility. We expect that high resolution proteomic analyses will reveal novel functions in single cells. This review provides an overview of recent developments in plant single-cell-type proteomics. We discuss application of the approach for understanding important cell functions, and we consider the technical challenges of extending the approach to all plant cell types. Finally, we consider the integration of single-cell-type proteomics with transcriptomics and metabolomics with the goal of providing a holistic understanding of plant function. PMID:22982375

The Impact of Child-Centered Group Play Therapy on Social Skills Development of Kindergarten Children

ERIC Educational Resources Information Center

Kascsak, Theresa Marie

2012-01-01

The development of social adjustment during elementary school is of critical importance because early socialization skills are an important predictor of both future social and emotional functioning. However, an examination of current literature reveals there is limited research utilizing sound research methodology and evaluation protocols for…

NMR Structural Profiling of Transcriptional Intermediates Reveals Riboswitch Regulation by Metastable RNA Conformations.

PubMed

Helmling, Christina; Wacker, Anna; Wolfinger, Michael T; Hofacker, Ivo L; Hengesbach, Martin; Fürtig, Boris; Schwalbe, Harald

2017-02-22

Gene repression induced by the formation of transcriptional terminators represents a prime example for the coupling of RNA synthesis, folding, and regulation. In this context, mapping the changes in available conformational space of transcription intermediates during RNA synthesis is important to understand riboswitch function. A majority of riboswitches, an important class of small metabolite-sensing regulatory RNAs, act as transcriptional regulators, but the dependence of ligand binding and the subsequent allosteric conformational switch on mRNA transcript length has not yet been investigated. We show a strict fine-tuning of binding and sequence-dependent alterations of conformational space by structural analysis of all relevant transcription intermediates at single-nucleotide resolution for the I-A type 2'dG-sensing riboswitch from Mesoplasma florum by NMR spectroscopy. Our results provide a general framework to dissect the coupling of synthesis and folding essential for riboswitch function, revealing the importance of metastable states for RNA-based gene regulation.

Differential subcellular distribution of ion channels and the diversity of neuronal function.

PubMed

Nusser, Zoltan

2012-06-01

Following the astonishing molecular diversity of voltage-gated ion channels that was revealed in the past few decades, the ion channel repertoire expressed by neurons has been implicated as the major factor governing their functional heterogeneity. Although the molecular structure of ion channels is a key determinant of their biophysical properties, their subcellular distribution and densities on the surface of nerve cells are just as important for fulfilling functional requirements. Recent results obtained with high resolution quantitative localization techniques revealed complex, subcellular compartment-specific distribution patterns of distinct ion channels. Here I suggest that within a given neuron type every ion channel has a unique cell surface distribution pattern, with the functional consequence that this dramatically increases the computational power of nerve cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

PubMed Central

Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; O'Seaghdha, Conall M.; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V.; O'Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D.; Gierman, Hinco J.; Feitosa, Mary; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Chouraki, Vincent; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B.; Launer, Lenore J.; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D.; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank B.; Demirkan, Ayse; Oostra, Ben A.; de Andrade, Mariza; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H.-Erich; Kolcic, Ivana; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E.; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H.; Wright, Alan F.; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Endlich, Karlhans; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K.; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Giulianini, Franco; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Metzger, Marie; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K.; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J. Wouter; Probst-Hensch, Nicole M.; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R.; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S.; van Duijn, Cornelia M.; Borecki, Ingrid; Kardia, Sharon L. R.; Liu, Yongmei; Curhan, Gary C.; Rudan, Igor; Gyllensten, Ulf; Wilson, James F.; Franke, Andre; Pramstaller, Peter P.; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline C. M.; Hayward, Caroline; Ridker, Paul; Parsa, Afshin; Bochud, Murielle; Heid, Iris M.; Goessling, Wolfram; Chasman, Daniel I.; Kao, W. H. Linda; Fox, Caroline S.

2012-01-01

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. PMID:22479191

Genome-wide association and functional follow-up reveals new loci for kidney function.

PubMed

Pattaro, Cristian; Köttgen, Anna; Teumer, Alexander; Garnaas, Maija; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C; O'Seaghdha, Conall M; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V; O'Connell, Jeffrey R; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D; Gierman, Hinco J; Feitosa, Mary; Hwang, Shih-Jen; Atkinson, Elizabeth J; Lohman, Kurt; Cornelis, Marilyn C; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Chouraki, Vincent; Holliday, Elizabeth G; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B; Launer, Lenore J; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank B; Demirkan, Ayse; Oostra, Ben A; de Andrade, Mariza; Turner, Stephen T; Ding, Jingzhong; Andrews, Jeanette S; Freedman, Barry I; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H-Erich; Kolcic, Ivana; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H; Wright, Alan F; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Endlich, Karlhans; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G; Rivadeneira, Fernando; Aulchenko, Yurii S; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Giulianini, Franco; Krämer, Bernhard K; Portas, Laura; Ford, Ian; Buckley, Brendan M; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Metzger, Marie; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J Wouter; Probst-Hensch, Nicole M; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S; van Duijn, Cornelia M; Borecki, Ingrid; Kardia, Sharon L R; Liu, Yongmei; Curhan, Gary C; Rudan, Igor; Gyllensten, Ulf; Wilson, James F; Franke, Andre; Pramstaller, Peter P; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline C M; Hayward, Caroline; Ridker, Paul; Parsa, Afshin; Bochud, Murielle; Heid, Iris M; Goessling, Wolfram; Chasman, Daniel I; Kao, W H Linda; Fox, Caroline S

2012-01-01

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

Segregated Systems of Human Brain Networks.

PubMed

Wig, Gagan S

2017-12-01

The organization of the brain network enables its function. Evaluation of this organization has revealed that large-scale brain networks consist of multiple segregated subnetworks of interacting brain areas. Descriptions of resting-state network architecture have provided clues for understanding the functional significance of these segregated subnetworks, many of which correspond to distinct brain systems. The present report synthesizes accumulating evidence to reveal how maintaining segregated brain systems renders the human brain network functionally specialized, adaptable to task demands, and largely resilient following focal brain damage. The organizational properties that support system segregation are harmonious with the properties that promote integration across the network, but confer unique and important features to the brain network that are central to its function and behavior. Copyright © 2017 Elsevier Ltd. All rights reserved.

Environmental drivers of the distribution of nitrogen functional genes at a watershed scale.

PubMed

Tsiknia, Myrto; Paranychianakis, Nikolaos V; Varouchakis, Emmanouil A; Nikolaidis, Nikolaos P

2015-06-01

To date only few studies have dealt with the biogeography of microbial communities at large spatial scales, despite the importance of such information to understand and simulate ecosystem functioning. Herein, we describe the biogeographic patterns of microorganisms involved in nitrogen (N)-cycling (diazotrophs, ammonia oxidizers, denitrifiers) as well as the environmental factors shaping these patterns across the Koiliaris Critical Zone Observatory, a typical Mediterranean watershed. Our findings revealed that a proportion of variance ranging from 40 to 80% of functional genes abundance could be explained by the environmental variables monitored, with pH, soil texture, total organic carbon and potential nitrification rate being identified as the most important drivers. The spatial autocorrelation of N-functional genes ranged from 0.2 to 6.2 km and prediction maps, generated by cokriging, revealed distinct patterns of functional genes. The inclusion of functional genes in statistical modeling substantially improved the proportion of variance explained by the models, a result possibly due to the strong relationships that were identified among microbial groups. Significant relationships were set between functional groups, which were further mediated by land use (natural versus agricultural lands). These relationships, in combination with the environmental variables, allow us to provide insights regarding the ecological preferences of N-functional groups and among them the recently identified clade II of nitrous oxide reducers. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Structure-function insights of membrane and soluble proteins revealed by electron crystallography.

PubMed

Dreaden, Tina M; Devarajan, Bharanidharan; Barry, Bridgette A; Schmidt-Krey, Ingeborg

2013-01-01

Electron crystallography is emerging as an important method in solving protein structures. While it has found extensive applications in the understanding of membrane protein structure and function at a wide range of resolutions, from revealing oligomeric arrangements to atomic models, electron crystallography has also provided invaluable information on the soluble α/β-tubulin which could not be obtained by any other method to date. Examples of critical insights from selected structures of membrane proteins as well as α/β-tubulin are described here, demonstrating the vast potential of electron crystallography that is first beginning to unfold.

Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding.

PubMed

Kanagarajadurai, Karuppiah; Malini, Manoharan; Bhattacharya, Aditi; Panicker, Mitradas M; Sowdhamini, Ramanathan

2009-12-01

The serotonergic system has been implicated in emotional and cognitive function. In particular, 5-HT(2A) (5-hydroxytrytamine receptor 2A) is attributed to a number of disorders like schizophrenia, depression, eating disorders and anxiety. 5-HT(2A), being a GPCR (G-protein coupled receptor), is important in the pharmaceutical industry as a proven target for these disorders. Despite their extensive clinical importance, the structural studies of this protein is lacking due to difficulties in determining its crystal structure. We have performed sequence analysis and molecular modeling of 5-HT(2A) that has revealed a set of conserved residues and motifs considered to play an important role in maintaining structural integrity and function of the receptor. The analysis also revealed a set of residues specific to the receptor which distinguishes them from other members of the subclass and their orthologs. Further, starting from the model structure of human 5-HT(2A) receptor, docking studies were attempted to envisage how it might interact with eight of its ligands (such as serotonin, dopamine, DOI, LSD, haloperidol, ketanserin, risperidone and clozapine). The binding studies of dopamine to 5-HT(2A) receptor can bring up better understanding in the etiology of a number of neurological disorders involving both these two receptors. Our sequence analysis and study of interactions of this receptor with other ligands reveal additional residue hotspots such as Asn 363 and Tyr 370. The function of these residues can be further analyzed by rational design of site-directed mutagenesis. Two distinct binding sites are identified which could play important roles in ligand binding and signaling.

OCTOPUS-LIKE 2, a novel player in Arabidopsis root and vascular development, reveals a key role for OCTOPUS family genes in root metaphloem sieve tube differentiation.

PubMed

Ruiz Sola, M Aguila; Coiro, Mario; Crivelli, Simona; Zeeman, Samuel C; Schmidt Kjølner Hansen, Signe; Truernit, Elisabeth

2017-12-01

Protophloem and metaphloem sieve tubes are essential for transporting carbohydrates and signalling molecules towards sink tissues. OCTOPUS (OPS) was previously identified as an important regulator of protophloem differentiation in Arabidopsis roots. Here, we investigated the role of OCTOPUS-LIKE 2 (OPL2), a gene homologous to OPS. OPL2 expression patterns were analysed, and functional equivalence of OPS and OPL2 was tested. Mutant and double mutant phenotypes were investigated. OPS and OPL2 displayed overlapping expression patterns and a high degree of functional overlap. A mutation in OPL2 revealed redundant functions of OPS and OPL2 in developmental processes in which OPS was known to play a role, notably cotyledon vascular patterning and protophloem development. Moreover, we also uncovered redundant roles for OPS and OPL2 in leaf vascular patterning and, most interestingly, metaphloem sieve tube differentiation. Our results reveal a novel OPS-like protein that, together with OPS, is an important regulator of vascular patterning, root growth and phloem development. OPS and OPL2 are the first genes identified that play a role in metaphloem sieve tube differentiation. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Genetic Interaction Maps in Escherichia coli Reveal Functional Crosstalk among Cell Envelope Biogenesis Pathways

PubMed Central

Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J.; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F.; Emili, Andrew

2011-01-01

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among >235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target. PMID:22125496

Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways.

PubMed

Babu, Mohan; Díaz-Mejía, J Javier; Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F; Emili, Andrew

2011-11-01

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target.

Correspondent Functional Topography of the Human Left Inferior Parietal Lobule at Rest and Under Task Revealed Using Resting-State fMRI and Coactivation Based Parcellation.

PubMed

Wang, Jiaojian; Xie, Sangma; Guo, Xin; Becker, Benjamin; Fox, Peter T; Eickhoff, Simon B; Jiang, Tianzi

2017-03-01

The human left inferior parietal lobule (LIPL) plays a pivotal role in many cognitive functions and is an important node in the default mode network (DMN). Although many previous studies have proposed different parcellation schemes for the LIPL, the detailed functional organization of the LIPL and the exact correspondence between the DMN and LIPL subregions remain unclear. Mounting evidence indicates that spontaneous fluctuations in the brain are strongly associated with cognitive performance at the behavioral level. However, whether a consistent functional topographic organization of the LIPL during rest and under task can be revealed remains unknown. Here, they used resting-state functional connectivity (RSFC) and task-related coactivation patterns separately to parcellate the LIPL and identified seven subregions. Four subregions were located in the supramarginal gyrus (SMG) and three subregions were located in the angular gyrus (AG). The subregion-specific networks and functional characterization revealed that the four anterior subregions were found to be primarily involved in sensorimotor processing, movement imagination and inhibitory control, audition perception and speech processing, and social cognition, whereas the three posterior subregions were mainly involved in episodic memory, semantic processing, and spatial cognition. The results revealed a detailed functional organization of the LIPL and suggested that the LIPL is a functionally heterogeneous area. In addition, the present study demonstrated that the functional architecture of the LIPL during rest corresponds with that found in task processing. Hum Brain Mapp 38:1659-1675, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

DOT1L regulates dystrophin expression and is critical for cardiac function

PubMed Central

Nguyen, Anh T.; Xiao, Bin; Neppl, Ronald L.; Kallin, Eric M.; Li, Juan; Chen, Taiping; Wang, Da-Zhi; Xiao, Xiao; Zhang, Yi

2011-01-01

Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin–glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease. PMID:21289070

Transcriptome mining and in silico structural and functional analysis of ascorbic acid and tartaric acid biosynthesis pathway enzymes in rose-scanted geranium.

PubMed

Narnoliya, Lokesh K; Sangwan, Rajender S; Singh, Sudhir P

2018-06-01

Rose-scented geranium (Pelargonium sp.) is widely known as aromatic and medicinal herb, accumulating specialized metabolites of high economic importance, such as essential oils, ascorbic acid, and tartaric acid. Ascorbic acid and tartaric acid are multifunctional metabolites of human value to be used as vital antioxidants and flavor enhancing agents in food products. No information is available related to the structural and functional properties of the enzymes involved in ascorbic acid and tartaric acid biosynthesis in rose-scented geranium. In the present study, transcriptome mining was done to identify full-length genes, followed by their bioinformatic and molecular modeling investigations and understanding of in silico structural and functional properties of these enzymes. Evolutionary conserved domains were identified in the pathway enzymes. In silico physicochemical characterization of the catalytic enzymes revealed isoelectric point (pI), instability index, aliphatic index, and grand average hydropathy (GRAVY) values of the enzymes. Secondary structural prediction revealed abundant proportion of alpha helix and random coil confirmations in the pathway enzymes. Three-dimensional homology models were developed for these enzymes. The predicted structures showed significant structural similarity with their respective templates in root mean square deviation analysis. Ramachandran plot analysis of the modeled enzymes revealed that more than 84% of the amino acid residues were within the favored regions. Further, functionally important residues were identified corresponding to catalytic sites located in the enzymes. To, our best knowledge, this is the first report which provides a foundation on functional annotation and structural determination of ascorbic acid and tartaric acid pathway enzymes in rose-scanted geranium.

Lifting the nebula: novel insights into skeletal muscle contractility.

PubMed

Ottenheijm, Coen A C; Granzier, Henk

2010-10-01

Nebulin is a giant protein and a constituent of the skeletal muscle sarcomere. The name of this protein refers to its unknown (i.e., nebulous) function. However, recent rapid advances reveal that nebulin plays important roles in the regulation of muscle contraction. When these functions of nebulin are compromised, muscle weakness ensues, as is the case in patients with nemaline myopathy.

A second trigeminal CGRP receptor: function and expression of the AMY1 receptor

PubMed Central

Walker, Christopher S; Eftekhari, Sajedeh; Bower, Rebekah L; Wilderman, Andrea; Insel, Paul A; Edvinsson, Lars; Waldvogel, Henry J; Jamaluddin, Muhammad A; Russo, Andrew F; Hay, Debbie L

2015-01-01

Objective The trigeminovascular system plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal system. Methods Receptor expression was determined using Taqman G protein-coupled receptor arrays and immunohistochemistry in trigeminal ganglia (TG) and the spinal trigeminal complex of the brainstem in rat and human. Receptor pharmacology was quantified using sensitive signaling assays in primary rat TG neurons. Results mRNA and histological expression analysis in rat and human samples revealed the presence of two CGRP-responsive receptors (AMY1: calcitonin receptor/receptor activity-modifying protein 1 [RAMP1]) and the CGRP receptor (calcitonin receptor-like receptor/RAMP1). In support of this finding, quantification of agonist and antagonist potencies revealed a dual population of functional CGRP-responsive receptors in primary rat TG neurons. Interpretation The unexpected presence of a functional non-canonical CGRP receptor (AMY1) at neural sites important for craniofacial pain has important implications for targeting the CGRP axis in migraine. PMID:26125036

Accounting for epistatic interactions improves the functional analysis of protein structures.

PubMed

Wilkins, Angela D; Venner, Eric; Marciano, David C; Erdin, Serkan; Atri, Benu; Lua, Rhonald C; Lichtarge, Olivier

2013-11-01

The constraints under which sequence, structure and function coevolve are not fully understood. Bringing this mutual relationship to light can reveal the molecular basis of binding, catalysis and allostery, thereby identifying function and rationally guiding protein redesign. Underlying these relationships are the epistatic interactions that occur when the consequences of a mutation to a protein are determined by the genetic background in which it occurs. Based on prior data, we hypothesize that epistatic forces operate most strongly between residues nearby in the structure, resulting in smooth evolutionary importance across the structure. We find that when residue scores of evolutionary importance are distributed smoothly between nearby residues, functional site prediction accuracy improves. Accordingly, we designed a novel measure of evolutionary importance that focuses on the interaction between pairs of structurally neighboring residues. This measure that we term pair-interaction Evolutionary Trace yields greater functional site overlap and better structure-based proteome-wide functional predictions. Our data show that the structural smoothness of evolutionary importance is a fundamental feature of the coevolution of sequence, structure and function. Mutations operate on individual residues, but selective pressure depends in part on the extent to which a mutation perturbs interactions with neighboring residues. In practice, this principle led us to redefine the importance of a residue in terms of the importance of its epistatic interactions with neighbors, yielding better annotation of functional residues, motivating experimental validation of a novel functional site in LexA and refining protein function prediction. lichtarge@bcm.edu. Supplementary data are available at Bioinformatics online.

Accounting for epistatic interactions improves the functional analysis of protein structures

PubMed Central

Wilkins, Angela D.; Venner, Eric; Marciano, David C.; Erdin, Serkan; Atri, Benu; Lua, Rhonald C.; Lichtarge, Olivier

2013-01-01

Motivation: The constraints under which sequence, structure and function coevolve are not fully understood. Bringing this mutual relationship to light can reveal the molecular basis of binding, catalysis and allostery, thereby identifying function and rationally guiding protein redesign. Underlying these relationships are the epistatic interactions that occur when the consequences of a mutation to a protein are determined by the genetic background in which it occurs. Based on prior data, we hypothesize that epistatic forces operate most strongly between residues nearby in the structure, resulting in smooth evolutionary importance across the structure. Methods and Results: We find that when residue scores of evolutionary importance are distributed smoothly between nearby residues, functional site prediction accuracy improves. Accordingly, we designed a novel measure of evolutionary importance that focuses on the interaction between pairs of structurally neighboring residues. This measure that we term pair-interaction Evolutionary Trace yields greater functional site overlap and better structure-based proteome-wide functional predictions. Conclusions: Our data show that the structural smoothness of evolutionary importance is a fundamental feature of the coevolution of sequence, structure and function. Mutations operate on individual residues, but selective pressure depends in part on the extent to which a mutation perturbs interactions with neighboring residues. In practice, this principle led us to redefine the importance of a residue in terms of the importance of its epistatic interactions with neighbors, yielding better annotation of functional residues, motivating experimental validation of a novel functional site in LexA and refining protein function prediction. Contact: lichtarge@bcm.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:24021383

Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation

PubMed Central

Wu, Xiao-nan; Shi, Tao-tao; He, Yao-hui; Wang, Fei-fei; Sang, Rui; Ding, Jian-cheng; Zhang, Wen-juan; Shu, Xing-yi; Shen, Hai-feng; Yi, Jia; Gao, Xiang; Liu, Wen

2017-01-01

Yin Yang 1 (YY1) is a multifunctional DNA-binding transcription factor shown to be critical in a variety of biological processes, and its activity and function have been shown to be regulated by multitude of mechanisms, which include but are not limited to post-translational modifications (PTMs), its associated proteins and cellular localization. YY2, the paralog of YY1 in mouse and human, has been proposed to function redundantly or oppositely in a context-specific manner compared with YY1. Despite its functional importance, how YY2’s DNA-binding activity and function are regulated, particularly by PTMs, remains completely unknown. Here we report the first PTM with functional characterization on YY2, namely lysine 247 monomethylation (K247me1), which was found to be dynamically regulated by SET7/9 and LSD1 both in vitro and in cultured cells. Functional study revealed that SET7/9-mediated YY2 methylation regulated its DNA-binding activity in vitro and in association with chromatin examined by chromatin immunoprecipitation coupled with sequencing (ChIP-seq) in cultured cells. Knockout of YY2, SET7/9 or LSD1 by CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9-mediated gene editing followed by RNA sequencing (RNA-seq) revealed that a subset of genes was positively regulated by YY2 and SET7/9, but negatively regulated by LSD1, which were enriched with genes involved in cell proliferation regulation. Importantly, YY2-regulated gene transcription, cell proliferation and tumor growth were dependent, at least partially, on YY2 K247 methylation. Finally, somatic mutations on YY2 found in cancer, which are in close proximity to K247, altered its methylation, DNA-binding activity and gene transcription it controls. Our findings revealed the first PTM with functional implications imposed on YY2 protein, and linked YY2 methylation with its biological functions. PMID:29098080

Interaction of ATP with a small heat shock protein from Mycobacterium leprae: effect on its structure and function.

PubMed

Nandi, Sandip Kumar; Chakraborty, Ayon; Panda, Alok Kumar; Ray, Sougata Sinha; Kar, Rajiv Kumar; Bhunia, Anirban; Biswas, Ashis

2015-03-01

Adenosine-5'-triphosphate (ATP) is an important phosphate metabolite abundantly found in Mycobacterium leprae bacilli. This pathogen does not derive ATP from its host but has its own mechanism for the generation of ATP. Interestingly, this molecule as well as several antigenic proteins act as bio-markers for the detection of leprosy. One such bio-marker is the 18 kDa antigen. This 18 kDa antigen is a small heat shock protein (HSP18) whose molecular chaperone function is believed to help in the growth and survival of the pathogen. But, no evidences of interaction of ATP with HSP18 and its effect on the structure and chaperone function of HSP18 are available in the literature. Here, we report for the first time evidences of "HSP18-ATP" interaction and its consequences on the structure and chaperone function of HSP18. TNP-ATP binding experiment and surface plasmon resonance measurement showed that HSP18 interacts with ATP with a sub-micromolar binding affinity. Comparative sequence alignment between M. leprae HSP18 and αB-crystallin identified the sequence 49KADSLDIDIE58 of HSP18 as the Walker-B ATP binding motif. Molecular docking studies revealed that β4-β8 groove/strands as an ATP interactive region in M. leprae HSP18. ATP perturbs the tertiary structure of HSP18 mildly and makes it less susceptible towards tryptic cleavage. ATP triggers exposure of additional hydrophobic patches at the surface of HSP18 and induces more stability against chemical and thermal denaturation. In vitro aggregation and thermal inactivation assays clearly revealed that ATP enhances the chaperone function of HSP18. Our studies also revealed that the alteration in the chaperone function of HSP18 is reversible and is independent of ATP hydrolysis. As the availability and binding of ATP to HSP18 regulates its chaperone function, this functional inflection may play an important role in the survival of M. leprae in hosts.

Molecular chaperones and photoreceptor function

PubMed Central

Kosmaoglou, Maria; Schwarz, Nele; Bett, John S.; Cheetham, Michael E.

2008-01-01

Molecular chaperones facilitate and regulate protein conformational change within cells. This encompasses many fundamental cellular processes: including the correct folding of nascent chains; protein transport and translocation; signal transduction and protein quality control. Chaperones are, therefore, important in several forms of human disease, including neurodegeneration. Within the retina, the highly specialized photoreceptor cell presents a fascinating paradigm to investigate the specialization of molecular chaperone function and reveals unique chaperone requirements essential to photoreceptor function. Mutations in several photoreceptor proteins lead to protein misfolding mediated neurodegeneration. The best characterized of these are mutations in the molecular light sensor, rhodopsin, which cause autosomal dominant retinitis pigmentosa. Rhodopsin biogenesis is likely to require chaperones, while rhodopsin misfolding involves molecular chaperones in quality control and the cellular response to protein aggregation. Furthermore, the specialization of components of the chaperone machinery to photoreceptor specific roles has been revealed by the identification of mutations in molecular chaperones that cause inherited retinal dysfunction and degeneration. These chaperones are involved in several important cellular pathways and further illuminate the essential and diverse roles of molecular chaperones. PMID:18490186

Morphological and functional aspects of progenitors perturbed in cortical malformations

PubMed Central

Bizzotto, Sara; Francis, Fiona

2015-01-01

In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area. PMID:25729350

TRPV2 enhances axon outgrowth through its activation by membrane stretch in developing sensory and motor neurons.

PubMed

Shibasaki, Koji; Murayama, Namie; Ono, Katsuhiko; Ishizaki, Yasuki; Tominaga, Makoto

2010-03-31

Thermosensitive TRP (thermo TRP) channels are well recognized for their contributions to sensory transduction, responding to a wide variety of stimuli including temperature, nociceptive stimuli, touch, and osmolarity. However, the precise roles for the thermo TRP channels during development have not been determined. To explore the functional importance of thermo TRP channels during neural development, the temporal expression was determined in embryonic mice. Interestingly, TRPV2 expression was detected in spinal motor neurons in addition to the dorsal root ganglia from embryonic day 10.5 and was localized in axon shafts and growth cones, suggesting that the channel is important for axon outgrowth regulation. We revealed that endogenous TRPV2 was activated in a membrane stretch-dependent manner in developing neurons by knocking down the TRPV2 function with dominant-negative TRPV2 and TRPV2-specific shRNA and significantly promoted axon outgrowth. Thus, for the first time we revealed that TRPV2 is an important regulator for axon outgrowth through its activation by membrane stretch during development.

How Costly is Hospital Quality? A Revealed-Preference Approach*

PubMed Central

Romley, John A.; Goldman, Dana P.

2013-01-01

We analyze the cost of quality improvement in hospitals, dealing with two challenges. Hospital quality is multidimensional and hard to measure, while unobserved productivity may influence quality supply. We infer the quality of hospitals in Los Angeles from patient choices. We then incorporate ‘revealed quality’ into a cost function, instrumenting with hospital demand. We find that revealed quality differentiates hospitals, but is not strongly correlated with clinical quality. Revealed quality is quite costly, and tends to increase with hospital productivity. Thus, non-clinical aspects of the hospital experience (perhaps including patient amenities) play important roles in hospital demand, competition, and costs. PMID:22299199

Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.

PubMed

Gautam, Mukesh; Jara, Javier H; Sekerkova, Gabriella; Yasvoina, Marina V; Martina, Marco; Özdinler, P Hande

2016-03-15

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated Alsin(KO)-UeGFP mice, by crossing Alsin(KO) and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability. © The Author 2016. Published by Oxford University Press.

Gene silencing reveals multiple functions of Na+/K+-ATPase in the salmon louse (Lepeophtheirus salmonis).

PubMed

Komisarczuk, Anna Z; Kongshaug, Heidi; Nilsen, Frank

2018-02-01

Na + /K + -ATPase has a key function in a variety of physiological processes including membrane excitability, osmoregulation, regulation of cell volume, and transport of nutrients. While knowledge about Na + /K + -ATPase function in osmoregulation in crustaceans is extensive, the role of this enzyme in other physiological and developmental processes is scarce. Here, we report characterization, transcriptional distribution and likely functions of the newly identified L. salmonis Na + /K + -ATPase (LsalNa + /K + -ATPase) α subunit in various developmental stages. The complete mRNA sequence was identified, with 3003 bp open reading frame encoding a putative protein of 1001 amino acids. Putative protein sequence of LsalNa + /K + -ATPase revealed all typical features of Na + /K + -ATPase and demonstrated high sequence identity to other invertebrate and vertebrate species. Quantitative RT-PCR analysis revealed higher LsalNa + /K + -ATPase transcript level in free-living stages in comparison to parasitic stages. In situ hybridization analysis of copepodids and adult lice revealed LsalNa + /K + -ATPase transcript localization in a wide variety of tissues such as nervous system, intestine, reproductive system, and subcuticular and glandular tissue. RNAi mediated knock-down of LsalNa + /K + -ATPase caused locomotion impairment, and affected reproduction and feeding. Morphological analysis of dsRNA treated animals revealed muscle degeneration in larval stages, severe changes in the oocyte formation and maturation in females and abnormalities in tegmental glands. Thus, the study represents an important foundation for further functional investigation and identification of physiological pathways in which Na + /K + -ATPase is directly or indirectly involved. Copyright © 2018 Elsevier Inc. All rights reserved.

The Importance of Barley Genetics and Domestication in a Global Perspective

PubMed Central

Pourkheirandish, Mohammad; Komatsuda, Takao

2007-01-01

Background Archaeological evidence has revealed that barley (Hordeum vulgare) is one of the oldest crops used by ancient farmers. Studies of the time and place of barley domestication may help in understanding ancient human civilization. Scope The studies of domesticated genes in crops have uncovered the mechanisms which converted wild and unpromising wild species to the most important food for humans. In addition to archaeological studies, molecular studies are finding new insights into the process of domestication. Throughout the process of barley domestication human selection on wild species resulted in plants with more harvestable seeds. One of the remarkable changes during barley domestications was the appearance of six-rowed barley. The gene associated with this trait results in three times more seed per spike compared with ancestral wild barley. This increase in number of seed resulted in a major dichotomy in the evolution of barley. The identification of the six-rowed spike gene provided a framework for understanding how this character was evolved. Some important barley domestication genes have been discovered and many are currently being investigated. Conclusions Identification of domestication genes in crops revealed that most of the drastic changes during domestication are the result of functional impairments in transcription factor genes, and creation of new functions is rare. Isolation of the six-rowed spike gene revealed that this trait was domesticated more than once in the domestication history of barley. Six-rowed barley is derived from two-rowed ancestral forms. Isolation of photoperiod-response genes in barley and rice revealed that different genes belonging to similar genetic networks partially control this trait. PMID:17761690

New aspects of grassland recovery in old-fields revealed by trait-based analyses of perennial-crop-mediated succession.

PubMed

Kelemen, András; Tóthmérész, Béla; Valkó, Orsolya; Miglécz, Tamás; Deák, Balázs; Török, Péter

2017-04-01

Classical old-field succession studies focused on vegetation changes after the abandonment of annual croplands or on succession after the elimination of cultivated crops. Perennial-crop-mediated succession, where fields are initially covered by perennial crops, reveals alternative aspects of old-field succession theories. We tested the validity of classical theories of old-field succession for perennial-crop-mediated succession. We formulated the following hypotheses: (1) functional diversity increases with increasing field age; (2) resource acquisition versus conservation trade-off shifts toward conservation at community level during the succession; (3) the importance of spatial and temporal seed dispersal decreases during the succession; and (4) competitiveness and stress-tolerance increases and ruderality decreases at community level during the succession. We studied functional diversity, trait distributions and plant strategies in differently aged old-fields using chronosequence method. We found increasing functional richness and functional divergence, but also unchanged or decreasing functional evenness. We detected a shift from resource acquisition to resource conservation strategy of communities during the succession. The role of spatial and temporal seed dispersal was found to be important not only at the initial but also at latter successional stages. We found an increasing stress-tolerance and a decreasing ruderality during succession, while the competitiveness remained unchanged at the community level. Despite the markedly different starting conditions, we found that classical and perennial-crop-mediated old-field successions have some similarities regarding the changes of functional diversity, resource acquisition versus conservation trade-off, and seed dispersal strategies. However, we revealed also the subsequent differences. The competitive character of communities remained stable during the succession; hence, the initial stages of perennial-crop-mediated succession can be similar to the middle stages of classical old-field succession. Moreover, the occupied functional niche space and differentiation were larger in the older stages, but resources were not effectively utilized within this space, suggesting that the stabilization of the vegetation requires more time.

Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells

PubMed Central

Fischer, Manuel; Horn, Sebastian; Belkacemi, Anouar; Kojer, Kerstin; Petrungaro, Carmelina; Habich, Markus; Ali, Muna; Küttner, Victoria; Bien, Melanie; Kauff, Frank; Dengjel, Jörn; Herrmann, Johannes M.; Riemer, Jan

2013-01-01

Oxidation of cysteine residues to disulfides drives import of many proteins into the intermembrane space of mitochondria. Recent studies in yeast unraveled the basic principles of mitochondrial protein oxidation, but the kinetics under physiological conditions is unknown. We developed assays to follow protein oxidation in living mammalian cells, which reveal that import and oxidative folding of proteins are kinetically and functionally coupled and depend on the oxidoreductase Mia40, the sulfhydryl oxidase augmenter of liver regeneration (ALR), and the intracellular glutathione pool. Kinetics of substrate oxidation depends on the amount of Mia40 and requires tightly balanced amounts of ALR. Mia40-dependent import of Cox19 in human cells depends on the inner membrane potential. Our observations reveal considerable differences in the velocities of mitochondrial import pathways: whereas preproteins with bipartite targeting sequences are imported within seconds, substrates of Mia40 remain in the cytosol for several minutes and apparently escape premature degradation and oxidation. PMID:23676665

Crystal Structure of the Pre-fusion Nipah Virus Fusion Glycoprotein Reveals a Novel Hexamer-of-Trimers Assembly.

PubMed

Xu, Kai; Chan, Yee-Peng; Bradel-Tretheway, Birgit; Akyol-Ataman, Zeynep; Zhu, Yongqun; Dutta, Somnath; Yan, Lianying; Feng, YanRu; Wang, Lin-Fa; Skiniotis, Georgios; Lee, Benhur; Zhou, Z Hong; Broder, Christopher C; Aguilar, Hector C; Nikolov, Dimitar B

2015-12-01

Nipah virus (NiV) is a paramyxovirus that infects host cells through the coordinated efforts of two envelope glycoproteins. The G glycoprotein attaches to cell receptors, triggering the fusion (F) glycoprotein to execute membrane fusion. Here we report the first crystal structure of the pre-fusion form of the NiV-F glycoprotein ectodomain. Interestingly this structure also revealed a hexamer-of-trimers encircling a central axis. Electron tomography of Nipah virus-like particles supported the hexameric pre-fusion model, and biochemical analyses supported the hexamer-of-trimers F assembly in solution. Importantly, structure-assisted site-directed mutagenesis of the interfaces between F trimers highlighted the functional relevance of the hexameric assembly. Shown here, in both cell-cell fusion and virus-cell fusion systems, our results suggested that this hexamer-of-trimers assembly was important during fusion pore formation. We propose that this assembly would stabilize the pre-fusion F conformation prior to cell attachment and facilitate the coordinated transition to a post-fusion conformation of all six F trimers upon triggering of a single trimer. Together, our data reveal a novel and functional pre-fusion architecture of a paramyxoviral fusion glycoprotein.

A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer.

PubMed

Gallon, Matthew; Clairfeuille, Thomas; Steinberg, Florian; Mas, Caroline; Ghai, Rajesh; Sessions, Richard B; Teasdale, Rohan D; Collins, Brett M; Cullen, Peter J

2014-09-02

The sorting nexin 27 (SNX27)-retromer complex is a major regulator of endosome-to-plasma membrane recycling of transmembrane cargos that contain a PSD95, Dlg1, zo-1 (PDZ)-binding motif. Here we describe the core interaction in SNX27-retromer assembly and its functional relevance for cargo sorting. Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. With disruption of SNX27 and retromer function linked to synaptic dysfunction and neurodegenerative disease, our work provides the first step, to our knowledge, in the molecular description of this important sorting complex, and more broadly describes a unique interaction between a PDZ domain and an arrestin-like fold.

A mechanism producing power law etc. distributions

NASA Astrophysics Data System (ADS)

Li, Heling; Shen, Hongjun; Yang, Bin

2017-07-01

Power law distribution is playing an increasingly important role in the complex system study. Based on the insolvability of complex systems, the idea of incomplete statistics is utilized and expanded, three different exponential factors are introduced in equations about the normalization condition, statistical average and Shannon entropy, with probability distribution function deduced about exponential function, power function and the product form between power function and exponential function derived from Shannon entropy and maximal entropy principle. So it is shown that maximum entropy principle can totally replace equal probability hypothesis. Owing to the fact that power and probability distribution in the product form between power function and exponential function, which cannot be derived via equal probability hypothesis, can be derived by the aid of maximal entropy principle, it also can be concluded that maximal entropy principle is a basic principle which embodies concepts more extensively and reveals basic principles on motion laws of objects more fundamentally. At the same time, this principle also reveals the intrinsic link between Nature and different objects in human society and principles complied by all.

Transmembrane domain dependent inhibitory function of FcγRIIB.

PubMed

Wang, Junyi; Li, Zongyu; Xu, Liling; Yang, Hengwen; Liu, Wanli

2018-03-01

FcγRIIB, the only inhibitory IgG Fc receptor, functions to suppress the hyper-activation of immune cells. Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of FcγRIIB. However, later studies revealed that in addition to the ITIM, the transmembrane (TM) domain of FcγRIIB is also indispensable for its inhibitory function. Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of FcγRIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE). In this review, we will summarize these epidemiological and functional studies of FcγRIIB-I232T in the past few years, and will further discuss the mechanisms accounting for the functional loss of FcγRIIB-I232T. Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of FcγRIIB and may provide insights to a new therapeutic target for the associated diseases.

Concordance Between Patient and Family Reports of Family Functioning in Bipolar I Disorder and Major Depressive Disorder

PubMed Central

Weinstock, Lauren M.; Wenze, Susan J.; Munroe, Mary K.; Miller, Ivan W.

2013-01-01

Despite the extensive literature on family functioning and mood disorders, less is known about concordance between patient- and family-reported family functioning. To address this question, adults with bipolar I disorder (BD; n = 92), major depressive disorder (MDD; n = 121), and their family members (ns = 135 and 201, respectively) were recruited from hospital sources. All patients and their family members completed the Family Assessment Device (Epstein et al., 1983). Intraclass correlation coefficients revealed that, in contrast to the moderate degree of concordance in the MDD sample, degree of concordance between patient- and family-reported family functioning was significantly weaker in BD. Subsequent analysis revealed that this discordance was driven by the reports of the child and young adolescent family members of the patients with BD. Results highlight the importance of collateral reports in the assessment of family functioning, especially among families of patients with BD, in research and treatment. PMID:23588224

Concordance between patient and family reports of family functioning in bipolar I disorder and major depressive disorder.

PubMed

Weinstock, Lauren M; Wenze, Susan J; Munroe, Mary K; Miller, Ivan W

2013-05-01

Despite the extensive literature on family functioning and mood disorders, less is known about concordance between patient- and family-reported family functioning. To address this question, adults with bipolar I disorder (BD; n = 92) or major depressive disorder (MDD; n = 121) and their family members (n = 135 and 201, respectively) were recruited from hospital sources. All patients and their family members completed the Family Assessment Device (Epstein, Baldwin, Bishop. J Marital Fam Ther. 9:171-180, 1983). Intraclass correlation coefficients revealed that, in contrast to the moderate degree of concordance in the MDD sample, degree of concordance between patient- and family-reported family functioning was significantly weaker in BD. Subsequent analysis revealed that this discordance was driven by the reports of the child and young adolescent family members of the patients with BD. Results highlight the importance of collateral reports in the assessment of family functioning, especially among families of patients with BD, in research and treatment.

Validation of Skeletal Muscle cis-Regulatory Module Predictions Reveals Nucleotide Composition Bias in Functional Enhancers

PubMed Central

Kwon, Andrew T.; Chou, Alice Yi; Arenillas, David J.; Wasserman, Wyeth W.

2011-01-01

We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions. PMID:22144875

Functional characterization of GmBZL2 (AtBZR1 like gene) reveals the conserved BR signaling regulation in Glycine max

PubMed Central

Zhang, Yu; Zhang, Yan-Jie; Yang, Bao-Jun; Yu, Xian-Xian; Wang, Dun; Zu, Song-Hao; Xue, Hong-Wei; Lin, Wen-Hui

2016-01-01

Brassinosteroids (BRs) play key roles in plant growth and development, and regulate various agricultural traits. Enhanced BR signaling leads to increased seed number and yield in Arabidopsis bzr1-1D (AtBZR1P234L, gain-of-function mutant of the important transcription factor in BR signaling/effects). BR signal transduction pathway is well elucidated in Arabidopsis but less known in other species. Soybean is an important dicot crop producing edible oil and protein. Phylogenetic analysis reveals AtBZR1-like genes are highly conserved in angiosperm and there are 4 orthologues in soybean (GmBZL1-4). We here report the functional characterization of GmBZL2 (relatively highly expresses in flowers). The P234 site in AtBZR1 is conserved in GmBZL2 (P216) and mutation of GmBZL2P216L leads to GmBZL2 accumulation. GmBZL2P216L (GmBZL2*) in Arabidopsis results in enhanced BR signaling; including increased seed number per silique. GmBZL2* partially rescued the defects of bri1-5, further demonstrating the conserved function of GmBZL2 with AtBZR1. BR treatment promotes the accumulation, nuclear localization and dephosphorylation/phosphorylation ratio of GmBZL2, revealing that GmBZL2 activity is regulated conservatively by BR signaling. Our studies not only indicate the conserved regulatory mechanism of GmBZL2 and BR signaling pathway in soybean, but also suggest the potential application of GmBZL2 in soybean seed yield. PMID:27498784

Functional characterization of GmBZL2 (AtBZR1 like gene) reveals the conserved BR signaling regulation in Glycine max.

PubMed

Zhang, Yu; Zhang, Yan-Jie; Yang, Bao-Jun; Yu, Xian-Xian; Wang, Dun; Zu, Song-Hao; Xue, Hong-Wei; Lin, Wen-Hui

2016-08-08

Brassinosteroids (BRs) play key roles in plant growth and development, and regulate various agricultural traits. Enhanced BR signaling leads to increased seed number and yield in Arabidopsis bzr1-1D (AtBZR1(P234L), gain-of-function mutant of the important transcription factor in BR signaling/effects). BR signal transduction pathway is well elucidated in Arabidopsis but less known in other species. Soybean is an important dicot crop producing edible oil and protein. Phylogenetic analysis reveals AtBZR1-like genes are highly conserved in angiosperm and there are 4 orthologues in soybean (GmBZL1-4). We here report the functional characterization of GmBZL2 (relatively highly expresses in flowers). The P234 site in AtBZR1 is conserved in GmBZL2 (P216) and mutation of GmBZL2(P216L) leads to GmBZL2 accumulation. GmBZL2(P216L) (GmBZL2*) in Arabidopsis results in enhanced BR signaling; including increased seed number per silique. GmBZL2* partially rescued the defects of bri1-5, further demonstrating the conserved function of GmBZL2 with AtBZR1. BR treatment promotes the accumulation, nuclear localization and dephosphorylation/phosphorylation ratio of GmBZL2, revealing that GmBZL2 activity is regulated conservatively by BR signaling. Our studies not only indicate the conserved regulatory mechanism of GmBZL2 and BR signaling pathway in soybean, but also suggest the potential application of GmBZL2 in soybean seed yield.

Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia

PubMed Central

Wu, Jing Qin; Wang, Xi; Beveridge, Natalie J.; Tooney, Paul A.; Scott, Rodney J.; Carr, Vaughan J.; Cairns, Murray J.

2012-01-01

Background While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression. Methodology/Principal Findings The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene. Conclusions This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia. PMID:22558445

Electrospun polymeric dressings functionalized with antimicrobial peptides and collagen type I for enhanced wound healing

NASA Astrophysics Data System (ADS)

Felgueiras, H. P.; Amorim, M. T. P.

2017-10-01

Modern wound dressings combine medical textiles with active compounds that stimulate wound healing while protecting against infection. Electrospun wound dressings have been extensively studied and the electrospinning technique recognized as an efficient approach for the production of nanoscale fibrous mats. The unique diverse function and architecture of antimicrobial peptides (AMPs) has attracted considerable attention as a tool for the design of new anti-infective drugs. Functionalizing electrospun wound dressings with these AMPs is nowadays being researched. In the present work, we explore these new systems by highlighting the most important characteristics of electropsun wound dressings, revealing the importance of AMPs to wound healing, and the methods available to functionalize the electrospun mats with these molecules. The combined therapeutic potential of collagen type I and these AMP functionalized dressings will be highlighted as well; the significance of these new strategies for the future of wound healing will be clarified.

Response of Microbial Community Function to Fluctuating Geochemical Conditions within a Legacy Radioactive Waste Trench Environment

PubMed Central

Kinsela, Andrew S.; Bligh, Mark W.; Harrison, Jennifer J.; Payne, Timothy E.

2017-01-01

ABSTRACT During the 1960s, small quantities of radioactive materials were codisposed with chemical waste at the Little Forest Legacy Site (Sydney, Australia) in 3-meter-deep, unlined trenches. Chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a 6-week period immediately after a prolonged rainfall event to assess the impact of changing water levels upon the microbial ecology and contaminant mobility. Collectively, results demonstrated that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the potentially important role that the taxonomically diverse microbial community played in this transition. In particular, aerobes dominated in the first day, followed by an increase of facultative anaerobes/denitrifiers at day 4. Toward the mid-end of the sampling period, the functional and taxonomic profiles depicted an anaerobic community distinguished by a higher representation of dissimilatory sulfate reduction and methanogenesis pathways. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs. IMPORTANCE The role of chemical and microbiological factors in mediating the biogeochemistry of groundwaters from trenches used to dispose of radioactive materials during the 1960s is examined in this study. Specifically, chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a 6-week period immediately after a prolonged rainfall event to assess how changing water levels influence microbial ecology and contaminant mobility. Results demonstrate that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the important role that the taxonomically diverse microbial community played in this transition. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs. PMID:28667104

Response of Microbial Community Function to Fluctuating Geochemical Conditions within a Legacy Radioactive Waste Trench Environment.

PubMed

Vázquez-Campos, Xabier; Kinsela, Andrew S; Bligh, Mark W; Harrison, Jennifer J; Payne, Timothy E; Waite, T David

2017-09-01

During the 1960s, small quantities of radioactive materials were codisposed with chemical waste at the Little Forest Legacy Site (Sydney, Australia) in 3-meter-deep, unlined trenches. Chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a 6-week period immediately after a prolonged rainfall event to assess the impact of changing water levels upon the microbial ecology and contaminant mobility. Collectively, results demonstrated that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the potentially important role that the taxonomically diverse microbial community played in this transition. In particular, aerobes dominated in the first day, followed by an increase of facultative anaerobes/denitrifiers at day 4. Toward the mid-end of the sampling period, the functional and taxonomic profiles depicted an anaerobic community distinguished by a higher representation of dissimilatory sulfate reduction and methanogenesis pathways. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs. IMPORTANCE The role of chemical and microbiological factors in mediating the biogeochemistry of groundwaters from trenches used to dispose of radioactive materials during the 1960s is examined in this study. Specifically, chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a 6-week period immediately after a prolonged rainfall event to assess how changing water levels influence microbial ecology and contaminant mobility. Results demonstrate that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the important role that the taxonomically diverse microbial community played in this transition. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs. Copyright © 2017 Vázquez-Campos et al.

Kinematic, dynamic, and thermodynamic impacts of hook-echo hydrometeors, including explorations into the utilization of polarimetric radar data

NASA Astrophysics Data System (ADS)

Askelson, Mark Anthony

Recent studies have revealed that the thermodynamic properties of the rear flank downdraft (RFD) may dictate whether or not a supercell becomes tornadic. Since hydrometeors are thought to be an important driving force for the RFD, it is postulated that they may be important to its thermodynamic properties and, possibly, to tornadogenesis. The role hook-echo hydrometeors play in driving RFDs is investigated by estimating hook-echo hydrometeor types and amounts from polarimetric radar data and by using that information to drive a relatively simple downdraft model. Soundings for the individual cases are used to initialize the downdraft model in order to replicate the environments of the storms as closely as possible. Since this effort and others like it require the quantitative utilization of radar data, issues pertaining to this are explored. In addition to analyses of coordinate transformation equations and an innovative objective analysis technique for weather radar data, the difficult problem of response functions for arbitrary weight functions and data distributions was considered. A novel approach to this problem revealed that the local response function for distance dependent weighted averaging schemes is the complex conjugate of the normalized Fourier transform of the effective weight function. This facilitates new research avenues, especially regarding analyses of irregularly spaced data. Simulations of hydrometeor driven RFDs show that hydrometeor fields inferred from radar data are able to drive significant downdrafts without the influence of vertical perturbation pressure gradients. Moreover, they reveal that above the boundary layer supercell environments are relatively resistant to downdrafts whereas within the boundary layer they are generally supportive of downdrafts. It appears that in many supercell environments relatively large hail (≥1 cm in diameter) or vertical perturbation pressure gradients may be needed to drive deep midlevel downdrafts that penetrate into the boundary layer. Because the boundary layer is an important downdraft generation/intensification layer, its thetae profile appears to be important to the surface RFD thetae deficit and, consequently, to tornadogenesis. To further examine these issues, analyses using idealized soundings that represent multiple possible RFD environments and analyses of the complete set of VORTEX cases are planned.

Psychiatric Symptoms due to Thyroid Disease in a Female Adolescent

PubMed Central

Capetillo-Ventura, Nelly; Baeza, Inmaculada

2014-01-01

The hypothalamic-pituitary-thyroid axis is involved in the production of thyroid hormone which is needed to maintain the normal functioning of various organs and systems, including the central nervous system. This study reports a case of hypothyroidism in a fifteen-year-old female adolescent who was attended for psychiatric symptoms. This case reveals the importance of evaluating thyroid function in children and adolescents with neuropsychiatric symptoms. PMID:25436160

Flavonoids function as antioxidants: By scavenging reactive oxygen species or by chelating iron?

NASA Astrophysics Data System (ADS)

Wuguo, Deng; Xingwang, Fang; Jilan, Wu

1997-09-01

Flavonoids have been reported to exhibit strong antioxidative activity. In the present work, a systematic mechanistic study has been performed on five flavonoids (baicalin, hesperidin, naringin, quercetin and rutin) selected according to their structural characteristics. The experimental results reveal that flavonoids function as antioxidant mainly by chelating iron ions and by scavenging peroxyl radicals whereas their OH radical scavenging effect is much less important.

Disentangling the influence of earthworms in sugarcane rhizosphere

PubMed Central

Braga, Lucas P. P.; Yoshiura, Caio A.; Borges, Clovis D.; Horn, Marcus A.; Brown, George G.; Drake, Harold L.; Tsai, Siu M.

2016-01-01

For the last 150 years many studies have shown the importance of earthworms for plant growth, but the exact mechanisms involved in the process are still poorly understood. Many important functions required for plant growth can be performed by soil microbes in the rhizosphere. To investigate earthworm influence on the rhizosphere microbial community, we performed a macrocosm experiment with and without Pontoscolex corethrurus (EW+ and EW−, respectively) and followed various soil and rhizosphere processes for 217 days with sugarcane. In EW+ treatments, N2O concentrations belowground (15 cm depth) and relative abundances of nitrous oxide genes (nosZ) were higher in bulk soil and rhizosphere, suggesting that soil microbes were able to consume earthworm-induced N2O. Shotgun sequencing (total DNA) revealed that around 70 microbial functions in bulk soil and rhizosphere differed between EW+ and EW− treatments. Overall, genes indicative of biosynthetic pathways and cell proliferation processes were enriched in EW+ treatments, suggesting a positive influence of worms. In EW+ rhizosphere, functions associated with plant-microbe symbiosis were enriched relative to EW− rhizosphere. Ecological networks inferred from the datasets revealed decreased niche diversification and increased keystone functions as an earthworm-derived effect. Plant biomass was improved in EW+ and worm population proliferated. PMID:27976685

Community assembly of the ferns of Florida.

PubMed

Sessa, Emily B; Chambers, Sally M; Li, Daijiang; Trotta, Lauren; Endara, Lorena; Burleigh, J Gordon; Baiser, Benjamin

2018-03-01

Many ecological and evolutionary processes shape the assembly of organisms into local communities from a regional pool of species. We analyzed phylogenetic and functional diversity to understand community assembly of the ferns of Florida at two spatial scales. We built a phylogeny for 125 of the 141 species of ferns in Florida using five chloroplast markers. We calculated mean pairwise dissimilarity (MPD) and mean nearest taxon distance (MNTD) from phylogenetic distances and functional trait data for both spatial scales and compared the results to null models to assess significance. Our results for over vs. underdispersion in functional and phylogenetic diversity differed depending on spatial scale and metric considered. At the county scale, MPD revealed evidence for phylogenetic overdispersion, while MNTD revealed phylogenetic and functional underdispersion, and at the conservation area scale, MPD revealed phylogenetic and functional underdispersion while MNTD revealed evidence only of functional underdispersion. Our results are consistent with environmental filtering playing a larger role at the smaller, conservation area scale. The smaller spatial units are likely composed of fewer local habitat types that are selecting for closely related species, with the larger-scale units more likely to be composed of multiple habitat types that bring together a larger pool of species from across the phylogeny. Several aspects of fern biology, including their unique physiology and water relations and the importance of the independent gametophyte stage of the life cycle, make ferns highly sensitive to local, microhabitat conditions. © 2018 The Authors. American Journal of Botany is published by Wiley Periodicals, Inc. on behalf of the Botanical Society of America.

PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells

PubMed Central

He, Feng; Chen, Hairong; Probst-Kepper, Michael; Geffers, Robert; Eifes, Serge; del Sol, Antonio; Schughart, Klaus; Zeng, An-Ping; Balling, Rudi

2012-01-01

Human FOXP3+CD25+CD4+ regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4+ T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function. PMID:23169000

Distributions of Bacterial Generalists among the Guts of Birds, Fish, and Mammals - abstract

EPA Science Inventory

Complex distributions of bacterial taxa within diverse animal microbiomes have inspired ecological and biogeographical approaches to revealing the functions of taxa that may be most important for host health. Of particular interest are bacteria that find many diverse habitats sui...

The Promise of a University.

ERIC Educational Resources Information Center

Cousins, Norman

1979-01-01

The function of the university is shown to be not only to train people but to educate them. The importance of creativity, longevity, and humor are discussed. Short conversations with Charles A. Beard, Albert Schweitzer, Nehru, and Krushchev reveal the essence of "What I've Learned." (MLW)

LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis.

PubMed

Thomas, James R; Gedeon, Patrick C; Grant, Barry J; Madura, Jeffry D

2012-07-03

Monoamine transporters (MATs) function by coupling ion gradients to the transport of dopamine, norepinephrine, or serotonin. Despite their importance in regulating neurotransmission, the exact conformational mechanism by which MATs function remains elusive. To this end, we have performed seven 250 ns accelerated molecular dynamics simulations of the leucine transporter, a model for neurotransmitter MATs. By varying the presence of binding-pocket leucine substrate and sodium ions, we have sampled plausible conformational states representative of the substrate transport cycle. The resulting trajectories were analyzed using principal component analysis of transmembrane helices 1b and 6a. This analysis revealed seven unique structures: two of the obtained conformations are similar to the currently published crystallographic structures, one conformation is similar to a proposed open inward structure, and four conformations represent novel structures of potential importance to the transport cycle. Further analysis reveals that the presence of binding-pocket sodium ions is necessary to stabilize the locked-occluded and open-inward conformations. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

A study on the natural history of scanning behaviour in patients with visual field defects after stroke.

PubMed

Loetscher, Tobias; Chen, Celia; Wignall, Sophie; Bulling, Andreas; Hoppe, Sabrina; Churches, Owen; Thomas, Nicole A; Nicholls, Michael E R; Lee, Andrew

2015-04-24

A visual field defect (VFD) is a common consequence of stroke with a detrimental effect upon the survivors' functional ability and quality of life. The identification of effective treatments for VFD is a key priority relating to life post-stroke. Understanding the natural evolution of scanning compensation over time may have important ramifications for the development of efficacious therapies. The study aims to unravel the natural history of visual scanning behaviour in patients with VFD. The assessment of scanning patterns in the acute to chronic stages of stroke will reveal who does and does not learn to compensate for vision loss. Eye-tracking glasses are used to delineate eye movements in a cohort of 100 stroke patients immediately after stroke, and additionally at 6 and 12 months post-stroke. The longitudinal study will assess eye movements in static (sitting) and dynamic (walking) conditions. The primary outcome constitutes the change of lateral eye movements from the acute to chronic stages of stroke. Secondary outcomes include changes of lateral eye movements over time as a function of subgroup characteristics, such as side of VFD, stroke location, stroke severity and cognitive functioning. The longitudinal comparison of patients who do and do not learn compensatory scanning techniques may reveal important prognostic markers of natural recovery. Importantly, it may also help to determine the most effective treatment window for visual rehabilitation.

Expanding the Definition of the Classical Bipartite Nuclear Localization Signal

PubMed Central

Lange, Allison; McLane, Laura M.; Mills, Ryan E.; Devine, Scott E.; Corbett, Anita H.

2010-01-01

Nuclear localization signals (NLSs) are amino acid sequences that target cargo proteins into the nucleus. Rigorous characterization of NLS motifs is essential to understanding and predicting pathways for nuclear import. The best-characterized NLS is the classical NLS (cNLS), which is recognized by the cNLS receptor, importin-α. cNLSs are conventionally defined as having one (monopartite) or two clusters of basic amino acids separated by a 9-12 amino acid linker (bipartite). Motivated by the finding that Ty1 integrase, which contains an unconventional putative bipartite cNLS with a 29 amino acid linker, exploits the classical nuclear import machinery, we assessed the functional boundaries for linker length within a bipartite cNLS. We confirmed that the integrase cNLS is a bona fide bipartite cNLS, then carried out a systematic analysis of linker length in an obligate bipartite cNLS cargo, which revealed that some linkers longer than conventionally defined can function in nuclear import. Linker function is dependent on the sequence and likely the inherent flexibility of the linker. Subsequently, we interrogated the Saccharomyces cerevisiae proteome to identify cellular proteins containing putative long bipartite cNLSs. We experimentally confirmed that Rrp4 contains a bipartite cNLS with a 25 amino acid linker. Our studies reveal that the traditional definition of bipartite cNLSs is too restrictive and linker length can vary depending on amino acid composition PMID:20028483

Horizontal gene transfer in silkworm, Bombyx mori.

PubMed

Zhu, Bo; Lou, Miao-Miao; Xie, Guan-Lin; Zhang, Guo-Qing; Zhou, Xue-Ping; Li, Bin; Jin, Gu-Lei

2011-05-19

The domesticated silkworm, Bombyx mori, is the model insect for the order Lepidoptera, has economically important values, and has gained some representative behavioral characteristics compared to its wild ancestor. The genome of B. mori has been fully sequenced while function analysis of BmChi-h and BmSuc1 genes revealed that horizontal gene transfer (HGT) maybe bestow a clear selective advantage to B. mori. However, the role of HGT in the evolutionary history of B. mori is largely unexplored. In this study, we compare the whole genome of B. mori with those of 382 prokaryotic and eukaryotic species to investigate the potential HGTs. Ten candidate HGT events were defined in B. mori by comprehensive sequence analysis using Maximum Likelihood and Bayesian method combining with EST checking. Phylogenetic analysis of the candidate HGT genes suggested that one HGT was plant-to- B. mori transfer while nine were bacteria-to- B. mori transfer. Furthermore, functional analysis based on expression, coexpression and related literature searching revealed that several HGT candidate genes have added important characters, such as resistance to pathogen, to B. mori. Results from this study clearly demonstrated that HGTs play an important role in the evolution of B. mori although the number of HGT events in B. mori is in general smaller than those of microbes and other insects. In particular, interdomain HGTs in B. mori may give rise to functional, persistent, and possibly evolutionarily significant new genes.

Targeting and assembly of components of the TOC protein import complex at the chloroplast outer envelope membrane

PubMed Central

Richardson, Lynn G. L.; Paila, Yamuna D.; Siman, Steven R.; Chen, Yi; Smith, Matthew D.; Schnell, Danny J.

2014-01-01

The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β–barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus. PMID:24966864

Targeting and assembly of components of the TOC protein import complex at the chloroplast outer envelope membrane.

PubMed

Richardson, Lynn G L; Paila, Yamuna D; Siman, Steven R; Chen, Yi; Smith, Matthew D; Schnell, Danny J

2014-01-01

The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β-barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

PubMed

Zhang, Ying-Ying; Li, Hai-Xia; Chen, Yin-Ying; Fang, Hong; Yu, Ya-Nan; Liu, Jun; Jing, Zhi-Wei; Wang, Zhong; Wang, Yong-Yan

2014-03-01

Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations. © 2013 John Wiley & Sons Ltd.

Functional Basis of Microorganism Classification.

PubMed

Zhu, Chengsheng; Delmont, Tom O; Vogel, Timothy M; Bromberg, Yana

2015-08-01

Correctly identifying nearest "neighbors" of a given microorganism is important in industrial and clinical applications where close relationships imply similar treatment. Microbial classification based on similarity of physiological and genetic organism traits (polyphasic similarity) is experimentally difficult and, arguably, subjective. Evolutionary relatedness, inferred from phylogenetic markers, facilitates classification but does not guarantee functional identity between members of the same taxon or lack of similarity between different taxa. Using over thirteen hundred sequenced bacterial genomes, we built a novel function-based microorganism classification scheme, functional-repertoire similarity-based organism network (FuSiON; flattened to fusion). Our scheme is phenetic, based on a network of quantitatively defined organism relationships across the known prokaryotic space. It correlates significantly with the current taxonomy, but the observed discrepancies reveal both (1) the inconsistency of functional diversity levels among different taxa and (2) an (unsurprising) bias towards prioritizing, for classification purposes, relatively minor traits of particular interest to humans. Our dynamic network-based organism classification is independent of the arbitrary pairwise organism similarity cut-offs traditionally applied to establish taxonomic identity. Instead, it reveals natural, functionally defined organism groupings and is thus robust in handling organism diversity. Additionally, fusion can use organism meta-data to highlight the specific environmental factors that drive microbial diversification. Our approach provides a complementary view to cladistic assignments and holds important clues for further exploration of microbial lifestyles. Fusion is a more practical fit for biomedical, industrial, and ecological applications, as many of these rely on understanding the functional capabilities of the microbes in their environment and are less concerned with phylogenetic descent.

Functional Basis of Microorganism Classification

PubMed Central

Zhu, Chengsheng; Delmont, Tom O.; Vogel, Timothy M.; Bromberg, Yana

2015-01-01

Correctly identifying nearest “neighbors” of a given microorganism is important in industrial and clinical applications where close relationships imply similar treatment. Microbial classification based on similarity of physiological and genetic organism traits (polyphasic similarity) is experimentally difficult and, arguably, subjective. Evolutionary relatedness, inferred from phylogenetic markers, facilitates classification but does not guarantee functional identity between members of the same taxon or lack of similarity between different taxa. Using over thirteen hundred sequenced bacterial genomes, we built a novel function-based microorganism classification scheme, functional-repertoire similarity-based organism network (FuSiON; flattened to fusion). Our scheme is phenetic, based on a network of quantitatively defined organism relationships across the known prokaryotic space. It correlates significantly with the current taxonomy, but the observed discrepancies reveal both (1) the inconsistency of functional diversity levels among different taxa and (2) an (unsurprising) bias towards prioritizing, for classification purposes, relatively minor traits of particular interest to humans. Our dynamic network-based organism classification is independent of the arbitrary pairwise organism similarity cut-offs traditionally applied to establish taxonomic identity. Instead, it reveals natural, functionally defined organism groupings and is thus robust in handling organism diversity. Additionally, fusion can use organism meta-data to highlight the specific environmental factors that drive microbial diversification. Our approach provides a complementary view to cladistic assignments and holds important clues for further exploration of microbial lifestyles. Fusion is a more practical fit for biomedical, industrial, and ecological applications, as many of these rely on understanding the functional capabilities of the microbes in their environment and are less concerned with phylogenetic descent. PMID:26317871

Integrating perspectives on vocal performance and consistency

PubMed Central

Sakata, Jon T.; Vehrencamp, Sandra L.

2012-01-01

SUMMARY Recent experiments in divergent fields of birdsong have revealed that vocal performance is important for reproductive success and under active control by distinct neural circuits. Vocal consistency, the degree to which the spectral properties (e.g. dominant or fundamental frequency) of song elements are produced consistently from rendition to rendition, has been highlighted as a biologically important aspect of vocal performance. Here, we synthesize functional, developmental and mechanistic (neurophysiological) perspectives to generate an integrated understanding of this facet of vocal performance. Behavioral studies in the field and laboratory have found that vocal consistency is affected by social context, season and development, and, moreover, positively correlated with reproductive success. Mechanistic investigations have revealed a contribution of forebrain and basal ganglia circuits and sex steroid hormones to the control of vocal consistency. Across behavioral, developmental and mechanistic studies, a convergent theme regarding the importance of vocal practice in juvenile and adult songbirds emerges, providing a basis for linking these levels of analysis. By understanding vocal consistency at these levels, we gain an appreciation for the various dimensions of song control and plasticity and argue that genes regulating the function of basal ganglia circuits and sex steroid hormones could be sculpted by sexual selection. PMID:22189763

Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition.

PubMed

Mahadevan, Vivek; Khademullah, C Sahara; Dargaei, Zahra; Chevrier, Jonah; Uvarov, Pavel; Kwan, Julian; Bagshaw, Richard D; Pawson, Tony; Emili, Andrew; De Koninck, Yves; Anggono, Victor; Airaksinen, Matti; Woodin, Melanie A

2017-10-13

KCC2 is a neuron-specific K + -Cl - cotransporter essential for establishing the Cl - gradient required for hyperpolarizing inhibition in the central nervous system (CNS). KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to human neurological disorders including epilepsy and neuropathic pain. Using functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with diverse proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons increases KCC2 expression and hyperpolarizes the reversal potential for Cl - . Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2.

Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

PubMed Central

Mahadevan, Vivek; Chevrier, Jonah; Uvarov, Pavel; Kwan, Julian; Bagshaw, Richard D; Pawson, Tony; Emili, Andrew; De Koninck, Yves; Anggono, Victor; Airaksinen, Matti

2017-01-01

KCC2 is a neuron-specific K+-Cl– cotransporter essential for establishing the Cl- gradient required for hyperpolarizing inhibition in the central nervous system (CNS). KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to human neurological disorders including epilepsy and neuropathic pain. Using functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with diverse proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons increases KCC2 expression and hyperpolarizes the reversal potential for Cl-. Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2. PMID:29028184

Possible roles of platelet-derived microparticles in atherosclerosis.

PubMed

Wang, Zhi-Ting; Wang, Zi; Hu, Yan-Wei

2016-05-01

Platelets and platelet-derived microparticles (PMPs) play important roles in cardiovascular diseases, especially atherosclerosis. Continued research has revealed that PMPs have numerous functions in atherosclerosis, not only in thrombosis formation, but also by induction of inflammation. PMPs also induce formation of foam cells. Recent evidence strongly indicates a significant role of PMPs in atherosclerosis. Here, current research on the function of PMPs in atherosclerosis is reviewed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Comparison of Preservice and Experienced Teachers' Perceptions of the School Psychologist.

ERIC Educational Resources Information Center

Dean, Raymond S.

1980-01-01

Experienced and preservice teachers agreed about the importance of the school psychologist and the appropriateness of referral problems. Analysis of ratings revealed that experienced teachers had a more negative opinion of the school psychologist's functioning when compared to their novice counterparts. (Author)

GENE EXPRESSION PROFILING IN AGING RATS AND MICE REVEALS CHANGES IN XENOBIOTIC METABOLISM GENES

EPA Science Inventory

Detoxification and elimination of xenobiotics are major functions of the liver and is important in maintaining the metabolic homeostasis of the organism. The degree to which aging affects hepatic metabolism is not known. The expression of xenobiotic metabolizing enzymes (XMEs), i...

Identification and functional analysis of the aspergillic acid gene cluster in Aspergillus flavus

USDA-ARS?s Scientific Manuscript database

Aspergillus flavus can colonize important food staples and produces aflatoxins, toxic and carcinogenic secondary metabolites. In silico analysis of the A. flavus genome revealed 56 gene clusters encoding for secondary metabolites. How these many of these metabolites affect fungal development, surviv...

[Possible effect of E-selectine on structure and function of arterial vessels in patients with metabolic syndrome].

PubMed

Voloshyna, O O; Lyzohub, V H; Romanenko, I M

2007-01-01

Endothelial dysfunction and endothelial cells activation as it was shown in patients with ischemic heart disease play important role in atherosclerosis progression and the development of cardiovascular events. Relationship between E-selectine and functional/ structural changes of the arterial vessels in patients with metabolic syndrome was not explored. We revealed that both activation of the endothelial cells and structural/functional changes of the arterial wall mostly depend on obesity and dislipedemia and in less extent on carbohydrates metabolism disorders.

Interaction of ATP with a Small Heat Shock Protein from Mycobacterium leprae: Effect on Its Structure and Function

PubMed Central

Nandi, Sandip Kumar; Chakraborty, Ayon; Panda, Alok Kumar; Sinha Ray, Sougata; Kar, Rajiv Kumar; Bhunia, Anirban; Biswas, Ashis

2015-01-01

Adenosine-5’-triphosphate (ATP) is an important phosphate metabolite abundantly found in Mycobacterium leprae bacilli. This pathogen does not derive ATP from its host but has its own mechanism for the generation of ATP. Interestingly, this molecule as well as several antigenic proteins act as bio-markers for the detection of leprosy. One such bio-marker is the 18 kDa antigen. This 18 kDa antigen is a small heat shock protein (HSP18) whose molecular chaperone function is believed to help in the growth and survival of the pathogen. But, no evidences of interaction of ATP with HSP18 and its effect on the structure and chaperone function of HSP18 are available in the literature. Here, we report for the first time evidences of “HSP18-ATP” interaction and its consequences on the structure and chaperone function of HSP18. TNP-ATP binding experiment and surface plasmon resonance measurement showed that HSP18 interacts with ATP with a sub-micromolar binding affinity. Comparative sequence alignment between M. leprae HSP18 and αB-crystallin identified the sequence 49KADSLDIDIE58 of HSP18 as the Walker-B ATP binding motif. Molecular docking studies revealed that β4-β8 groove/strands as an ATP interactive region in M. leprae HSP18. ATP perturbs the tertiary structure of HSP18 mildly and makes it less susceptible towards tryptic cleavage. ATP triggers exposure of additional hydrophobic patches at the surface of HSP18 and induces more stability against chemical and thermal denaturation. In vitro aggregation and thermal inactivation assays clearly revealed that ATP enhances the chaperone function of HSP18. Our studies also revealed that the alteration in the chaperone function of HSP18 is reversible and is independent of ATP hydrolysis. As the availability and binding of ATP to HSP18 regulates its chaperone function, this functional inflection may play an important role in the survival of M. leprae in hosts. PMID:25811190

The Impact of Ocean Acidification on the Functional Morphology of Foraminifera

PubMed Central

Khanna, Nikki; Godbold, Jasmin A.; Austin, William E. N.; Paterson, David M.

2013-01-01

Culturing experiments were performed on sediment samples from the Ythan Estuary, N. E. Scotland, to assess the impacts of ocean acidification on test surface ornamentation in the benthic foraminifer Haynesina germanica. Specimens were cultured for 36 weeks at either 380, 750 or 1000 ppm atmospheric CO2. Analysis of the test surface using SEM imaging reveals sensitivity of functionally important ornamentation associated with feeding to changing seawater CO2 levels. Specimens incubated at high CO2 levels displayed evidence of shell dissolution, a significant reduction and deformation of ornamentation. It is clear that these calcifying organisms are likely to be vulnerable to ocean acidification. A reduction in functionally important ornamentation could lead to a reduction in feeding efficiency with consequent impacts on this organism's survival and fitness. PMID:24358253

Is a healthy ecosystem one that is rich in parasites?

USGS Publications Warehouse

Hudson, Peter J.; Dobson, Andrew P.; Lafferty, Kevin D.

2006-01-01

Historically, the role of parasites in ecosystem functioning has been considered trivial because a cursory examination reveals that their relative biomass is low compared with that of other trophic groups. However there is increasing evidence that parasite-mediated effects could be significant: they shape host population dynamics, alter interspecific competition, influence energy flow and appear to be important drivers of biodiversity. Indeed they influence a range of ecosystem functions and have a major effect on the structure of some food webs. Here, we consider the bottom-up and top-down processes of how parasitism influences ecosystem functioning and show that there is evidence that parasites are important for biodiversity and production; thus, we consider a healthy system to be one that is rich in parasite species.

BamA β16C strand and periplasmic turns are critical for outer membrane protein insertion and assembly.

PubMed

Gu, Yinghong; Zeng, Yi; Wang, Zhongshan; Dong, Changjiang

2017-11-21

Outer membrane (OM) β-barrel proteins play important roles in importing nutrients, exporting wastes and conducting signals in Gram-negative bacteria, mitochondria and chloroplasts. The outer membrane proteins (OMPs) are inserted and assembled into the OM by OMP85 family proteins. In Escherichia coli , the β-barrel assembly machinery (BAM) contains four lipoproteins such as BamB, BamC, BamD and BamE, and one OMP BamA, forming a 'top hat'-like structure. Structural and functional studies of the E. coli BAM machinery have revealed that the rotation of periplasmic ring may trigger the barrel β1C-β6C scissor-like movement that promote the unfolded OMP insertion without using ATP. Here, we report the BamA C-terminal barrel structure of Salmonella enterica Typhimurium str. LT2 and functional assays, which reveal that the BamA's C-terminal residue Trp, the β16C strand of the barrel and the periplasmic turns are critical for the functionality of BamA. These findings indicate that the unique β16C strand and the periplasmic turns of BamA are important for the outer membrane insertion and assembly. The periplasmic turns might mediate the rotation of the periplasmic ring to the scissor-like movement of BamA β1C-β6C, triggering the OMP insertion. These results are important for understanding the OMP insertion in Gram-negative bacteria, as well as in mitochondria and chloroplasts. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

All-atom molecular dynamics of the HBV capsid reveals insights into biological function and cryo-EM resolution limits

PubMed Central

Perilla, Juan R; Schlicksup, Christopher John; Venkatakrishnan, Balasubramanian; Zlotnick, Adam; Schulten, Klaus

2018-01-01

The hepatitis B virus capsid represents a promising therapeutic target. Experiments suggest the capsid must be flexible to function; however, capsid structure and dynamics have not been thoroughly characterized in the absence of icosahedral symmetry constraints. Here, all-atom molecular dynamics simulations are leveraged to investigate the capsid without symmetry bias, enabling study of capsid flexibility and its implications for biological function and cryo-EM resolution limits. Simulation results confirm flexibility and reveal a propensity for asymmetric distortion. The capsid’s influence on ionic species suggests a mechanism for modulating the display of cellular signals and implicates the capsid’s triangular pores as the location of signal exposure. A theoretical image reconstruction performed using simulated conformations indicates how capsid flexibility may limit the resolution of cryo-EM. Overall, the present work provides functional insight beyond what is accessible to experimental methods and raises important considerations regarding asymmetry in structural studies of icosahedral virus capsids. PMID:29708495

The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function.

PubMed

Gu, Yue; Jones, Amanda E; Yang, Wei; Liu, Shanrun; Dai, Qian; Liu, Yudong; Swindle, C Scott; Zhou, Dewang; Zhang, Zhuo; Ryan, Thomas M; Townes, Tim M; Klug, Christopher A; Chen, Dongquan; Wang, Hengbin

2016-01-05

Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation.

Integrating community assembly and biodiversity to better understand ecosystem function: the Community Assembly and the Functioning of Ecosystems (CAFE) approach.

PubMed

Bannar-Martin, Katherine H; Kremer, Colin T; Ernest, S K Morgan; Leibold, Mathew A; Auge, Harald; Chase, Jonathan; Declerck, Steven A J; Eisenhauer, Nico; Harpole, Stanley; Hillebrand, Helmut; Isbell, Forest; Koffel, Thomas; Larsen, Stefano; Narwani, Anita; Petermann, Jana S; Roscher, Christiane; Cabral, Juliano Sarmento; Supp, Sarah R

2018-02-01

The research of a generation of ecologists was catalysed by the recognition that the number and identity of species in communities influences the functioning of ecosystems. The relationship between biodiversity and ecosystem functioning (BEF) is most often examined by controlling species richness and randomising community composition. In natural systems, biodiversity changes are often part of a bigger community assembly dynamic. Therefore, focusing on community assembly and the functioning of ecosystems (CAFE), by integrating both species richness and composition through species gains, losses and changes in abundance, will better reveal how community changes affect ecosystem function. We synthesise the BEF and CAFE perspectives using an ecological application of the Price equation, which partitions the contributions of richness and composition to function. Using empirical examples, we show how the CAFE approach reveals important contributions of composition to function. These examples show how changes in species richness and composition driven by environmental perturbations can work in concert or antagonistically to influence ecosystem function. Considering how communities change in an integrative fashion, rather than focusing on one axis of community structure at a time, will improve our ability to anticipate and predict changes in ecosystem function. © 2017 The Authors. Ecology Letters published by CNRS and John Wiley & Sons Ltd.

Social Function in Multiple X and Y Chromosome Disorders: XXY, XYY, XXYY, XXXY

PubMed Central

Visootsak, Jeannie; Graham, John M.

2014-01-01

Klinefelter syndrome (47,XXY) was initially described in the context of its endocrinologic and physical features; however, subsequent studies have revealed specific impairments in verbal skills and social functioning. Males with sex chromosomal aneuploidies are known to have variability in their developmental profile with the majority presenting with expressive language deficits. As a consequence of language delays, they have an increased likelihood of language-based learning disabilities and social-emotional problems that may persist through adulthood. Studies on males with 47,XXY have revealed unique behavioral and social profiles with possible vulnerability to autistic traits. The prevalence of males with more than one extra sex chromosome (e.g., 48,XXYY and 48,XXXY) and an additional Y (e.g., 47,XYY) is less common, but it is important to understand their social functioning as it provides insight into treatment implications. PMID:20014367

Genetic randomization reveals functional relationships among morphologic and tissue-quality traits that contribute to bone strength and fragility

PubMed Central

Hu, Bin; Tommasini, Steven M.; Courtland, Hayden-William; Price, Christopher; Terranova, Carl J.; Nadeau, Joseph H.

2007-01-01

We examined femora from adult AXB/BXA recombinant inbred (RI) mouse strains to identify skeletal traits that are functionally related and to determine how functional interactions among these traits contribute to genetic variability in whole-bone stiffness, strength, and toughness. Randomization of A/J and C57BL/6J genomic regions resulted in each adult male and female RI strain building mechanically functional femora by assembling unique sets of morphologic and tissue-quality traits. A correlation analysis was conducted using the mean trait values for each RI strain. A third of the 66 correlations examined were significant, indicating that many bone traits covaried or were functionally related. Path analysis revealed important functional interactions among bone slenderness, cortical thickness, and tissue mineral density. The path coefficients describing these functional relations were similar for both sexes. The causal relationship among these three traits suggested that cellular processes during growth simultaneously regulate bone slenderness, cortical thickness, and tissue mineral density so that the combination of traits is sufficiently stiff and strong to satisfy daily loading demands. A disadvantage of these functional interactions was that increases in tissue mineral density also deleteriously affected tissue ductility. Consequently, slender bones with high mineral density may be stiff and strong but they are also brittle. Thus, genetically randomized mouse strains revealed a basic biological paradigm that allows for flexibility in building bones that are functional for daily activities but that creates preferred sets of traits under extreme loading conditions. Genetic or environmental perturbations that alter these functional interactions during growth would be expected to lead to loss of function and suboptimal adult bone quality. PMID:17557179

Reconstruction of the domain orientation distribution function of polycrystalline PZT ceramics using vector piezoresponse force microscopy.

PubMed

Kratzer, Markus; Lasnik, Michael; Röhrig, Sören; Teichert, Christian; Deluca, Marco

2018-01-11

Lead zirconate titanate (PZT) is one of the prominent materials used in polycrystalline piezoelectric devices. Since the ferroelectric domain orientation is the most important parameter affecting the electromechanical performance, analyzing the domain orientation distribution is of great importance for the development and understanding of improved piezoceramic devices. Here, vector piezoresponse force microscopy (vector-PFM) has been applied in order to reconstruct the ferroelectric domain orientation distribution function of polished sections of device-ready polycrystalline lead zirconate titanate (PZT) material. A measurement procedure and a computer program based on the software Mathematica have been developed to automatically evaluate the vector-PFM data for reconstructing the domain orientation function. The method is tested on differently in-plane and out-of-plane poled PZT samples, and the results reveal the expected domain patterns and allow determination of the polarization orientation distribution function at high accuracy.

Aquaporin structure-function relationships: water flow through plant living cells.

PubMed

Zhao, Chang-Xing; Shao, Hong-Bo; Chu, Li-Ye

2008-04-01

Plant aquaporins play an important role in water uptake and movement-an aquaporin that opens and closes a gate that regulates water movement in and out of cells. Some plant aquaporins also play an important role in response to water stress. Since their discovery, advancing knowledge of their structures and properties led to an understanding of the basic features of the water transport mechanism and increased illumination to water relations. Meanwhile, molecular and functional characterization of aquaporins has revealed the significance of their regulation in response to the adverse environments such as salinity and drought. This paper reviews the structure, species diversity, physiology function, regulation of plant aquaporins, and the relations between environmental factors and plant aquaporins. Complete understanding of aquaporin function and regulation is to integrate those mechanisms in time and space and to well regulate the permeation of water across biological membranes under changing environmental and developmental conditions.

Form follows function: the importance of endoplasmic reticulum shape.

PubMed

Westrate, L M; Lee, J E; Prinz, W A; Voeltz, G K

2015-01-01

The endoplasmic reticulum (ER) has a remarkably complex structure, composed of a single bilayer that forms the nuclear envelope, along with a network of sheets and dynamic tubules. Our understanding of the biological significance of the complex architecture of the ER has improved dramatically in the last few years. The identification of proteins and forces required for maintaining ER shape, as well as more advanced imaging techniques, has allowed the relationship between ER shape and function to come into focus. These studies have also revealed unexpected new functions of the ER and novel ER domains regulating alterations in ER dynamics. The importance of ER structure has become evident as recent research has identified diseases linked to mutations in ER-shaping proteins. In this review, we discuss what is known about the maintenance of ER architecture, the relationship between ER structure and function, and diseases associated with defects in ER structure.

A computational prediction of structure and function of novel homologue of Arabidopsis thaliana Vps51/Vps67 subunit in Corchorus olitorius.

PubMed

Zaman, Aubhishek; Fancy, Nurun Nahar

2012-12-01

Vps mediated vesicular transport is important for transferring macromolecules trapped inside a vesicle. Although highly abundant, Vps shows tremendous sequence variation among diverse array of species. However, this difference in sequence, which seems to also translate into substantial functional variation, is hardly characterized in Corchorus spp. Here, our computational study investigates structural and functional features of one of the Vps subunit namely Vps51/Vps67 in C. olitorius. Broad scale structural characterization revealed novel information about the overall Vps structure and binding sites. Moreover, functional analyses indicate interaction partners which were unexplored to date. Since membrane trafficking is essentially associated with nutrient uptake and chemical de-toxification, characterization of the Vps subunit can well provide us with better insight into important agronomic traits such as stress response, immune response and phytoremediation capacity.

Phylogenetic and Protein Sequence Analysis of Bacterial Chemoreceptors.

PubMed

Ortega, Davi R; Zhulin, Igor B

2018-01-01

Identifying chemoreceptors in sequenced bacterial genomes, revealing their domain architecture, inferring their evolutionary relationships, and comparing them to chemoreceptors of known function become important steps in genome annotation and chemotaxis research. Here, we describe bioinformatics procedures that enable such analyses, using two closely related bacterial genomes as examples.

Analysis of Globodera rostochiensis effectors reveals conserved functions of SPRYSEC proteins in suppressing and eliciting plant immune responses

USDA-ARS?s Scientific Manuscript database

Potato cyst nematodes (PCNs), including Globodera rostochiensis (Woll.), are important pests of potato. Plant parasitic nematodes produce multiple effector proteins, secreted from their stylets, to successfully infect their hosts. These include proteins that are delivered to the apoplast, as well as...

Analyzing Online Behaviors, Roles, and Learning Communities via Online Discussions

ERIC Educational Resources Information Center

Yeh, Yu-Chu

2010-01-01

Online learning communities are an important means of sharing and creating knowledge. Online behaviors and online roles can reveal how online learning communities function. However, no study has elucidated the relationships among online behaviors, online roles, and online learning communities. In this study, 32 preservice teachers participated in…

Media Literacy Function in Critical Blogs

ERIC Educational Resources Information Center

Fedorov, Alexander; Levitskaya, Anastasia

2015-01-01

The Internet is widely recognized as playing an important role in facilitating education on a range of issues, including media literacy. Analyzing the media critical activity of contemporary Russian bloggers, the authors of the article reveal the following reasons for popularity or, on the contrary, unpopularity of blogger's media criticism:…

Multinational Scanning: A Study of the Information Sources Utilized by Headquarters Executives in Multinational Companies

ERIC Educational Resources Information Center

Keegan, Warren J.

1974-01-01

Findings reveal the great importance of human sources of information and sources outside the organization. Divisional boundaries, functional specialization, and level were all found to act as significant barriers to information flows, and thus as limitations to organizational effectiveness. (Author/WM)

Comparative Metabolomics of Mycoplasma bovis and Mycoplasma gallisepticum Reveals Fundamental Differences in Active Metabolic Pathways and Suggests Novel Gene Annotations.

PubMed

Masukagami, Y; De Souza, D P; Dayalan, S; Bowen, C; O'Callaghan, S; Kouremenos, K; Nijagal, B; Tull, D; Tivendale, K A; Markham, P F; McConville, M J; Browning, G F; Sansom, F M

2017-01-01

Mycoplasmas are simple, but successful parasites that have the smallest genome of any free-living cell and are thought to have a highly streamlined cellular metabolism. Here, we have undertaken a detailed metabolomic analysis of two species, Mycoplasma bovis and Mycoplasma gallisepticum , which cause economically important diseases in cattle and poultry, respectively. Untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses of mycoplasma metabolite extracts revealed significant differences in the steady-state levels of many metabolites in central carbon metabolism, while 13 C stable isotope labeling studies revealed marked differences in carbon source utilization. These data were mapped onto in silico metabolic networks predicted from genome wide annotations. The analyses elucidated distinct differences, including a clear difference in glucose utilization, with a marked decrease in glucose uptake and glycolysis in M. bovis compared to M. gallisepticum , which may reflect differing host nutrient availabilities. The 13 C-labeling patterns also revealed several functional metabolic pathways that were previously unannotated in these species, allowing us to assign putative enzyme functions to the products of a number of genes of unknown function, especially in M. bovis . This study demonstrates the considerable potential of metabolomic analyses to assist in characterizing significant differences in the metabolism of different bacterial species and in improving genome annotation. IMPORTANCE Mycoplasmas are pathogenic bacteria that cause serious chronic infections in production animals, resulting in considerable losses worldwide, as well as causing disease in humans. These bacteria have extremely reduced genomes and are thought to have limited metabolic flexibility, even though they are highly successful persistent parasites in a diverse number of species. The extent to which different Mycoplasma species are capable of catabolizing host carbon sources and nutrients, or synthesizing essential metabolites, remains poorly defined. We have used advanced metabolomic techniques to identify metabolic pathways that are active in two species of Mycoplasma that infect distinct hosts (poultry and cattle). We show that these species exhibit marked differences in metabolite steady-state levels and carbon source utilization. This information has been used to functionally characterize previously unknown genes in the genomes of these pathogens. These species-specific differences are likely to reflect important differences in host nutrient levels and pathogenic mechanisms.

Global analysis of human duplicated genes reveals the relative importance of whole-genome duplicates originated in the early vertebrate evolution.

PubMed

Acharya, Debarun; Ghosh, Tapash C

2016-01-22

Gene duplication is a genetic mutation that creates functionally redundant gene copies that are initially relieved from selective pressures and may adapt themselves to new functions with time. The levels of gene duplication may vary from small-scale duplication (SSD) to whole genome duplication (WGD). Studies with yeast revealed ample differences between these duplicates: Yeast WGD pairs were functionally more similar, less divergent in subcellular localization and contained a lesser proportion of essential genes. In this study, we explored the differences in evolutionary genomic properties of human SSD and WGD genes, with the identifiable human duplicates coming from the two rounds of whole genome duplication occurred early in vertebrate evolution. We observed that these two groups of duplicates were also dissimilar in terms of their evolutionary and genomic properties. But interestingly, this is not like the same observed in yeast. The human WGDs were found to be functionally less similar, diverge more in subcellular level and contain a higher proportion of essential genes than the SSDs, all of which are opposite from yeast. Additionally, we explored that human WGDs were more divergent in their gene expression profile, have higher multifunctionality and are more often associated with disease, and are evolutionarily more conserved than human SSDs. Our study suggests that human WGD duplicates are more divergent and entails the adaptation of WGDs to novel and important functions that consequently lead to their evolutionary conservation in the course of evolution.

The TiPS/TINS lecture: the molecular biology of mammalian glutamate receptor channels.

PubMed

Seeburg, P H

1993-08-01

In native brain membranes the principal excitatory neurotransmitter L-glutamate activates cation-conducting channels with distinct biophysical and pharmacological properties. Molecular cloning has revealed the existence of 16 channel subunits that can assemble in homomeric or heteromeric configurations in vitro to form receptor channels with disparate functional properties. This review describes the different channel types obtained by recombinant means and the genetic mechanisms controlling the expression of functionally important channel structures.

The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels.

PubMed

Seeburg, P H

1993-09-01

In native brain membranes the principal excitatory neurotransmitter L-glutamate activates cation-conducting channels with distinct biophysical and pharmacological properties. Molecular cloning has revealed the existence of 16 channel subunits that can assemble in homomeric or heteromeric configurations in vitro to form receptor channels with disparate functional properties. This review describes the different channel types obtained by recombinant means and the genetic mechanisms controlling the expression of functionally important channel structures.

Striatal changes in Parkinson disease: An investigation of morphology, functional connectivity and their relationship to clinical symptoms.

PubMed

Owens-Walton, Conor; Jakabek, David; Li, Xiaozhen; Wilkes, Fiona A; Walterfang, Mark; Velakoulis, Dennis; van Westen, Danielle; Looi, Jeffrey C L; Hansson, Oskar

2018-05-30

We sought to investigate morphological and resting state functional connectivity changes to the striatal nuclei in Parkinson disease (PD) and examine whether changes were associated with measures of clinical function. Striatal nuclei were manually segmented on 3T-T1 weighted MRI scans of 74 PD participants and 27 control subjects, quantitatively analysed for volume, shape and also functional connectivity using functional MRI data. Bilateral caudate nuclei and putamen volumes were significantly reduced in the PD cohort compared to controls. When looking at left and right hemispheres, the PD cohort had significantly smaller left caudate nucleus and right putamen volumes compared to controls. A significant correlation was found between greater atrophy of the caudate nucleus and poorer cognitive function, and between greater atrophy of the putamen and more severe motor symptoms. Resting-state functional MRI analysis revealed altered functional connectivity of the striatal structures in the PD group. This research demonstrates that PD involves atrophic changes to the caudate nucleus and putamen that are linked to clinical dysfunction. Our work reveals important information about a key structure-function relationship in the brain and provides support for caudate nucleus and putamen atrophy as neuroimaging biomeasures in PD. Copyright © 2018 Elsevier B.V. All rights reserved.

A novel analysis strategy for integrating methylation and expression data reveals core pathways for thyroid cancer aetiology

PubMed Central

2015-01-01

Background Recently, a wide range of diseases have been associated with changes in DNA methylation levels, which play a vital role in gene expression regulation. With ongoing developments in technology, attempts to understand disease mechanism have benefited greatly from epigenetics and transcriptomics studies. In this work, we have used expression and methylation data of thyroid carcinoma as a case study and explored how to optimally incorporate expression and methylation information into the disease study when both data are available. Moreover, we have also investigated whether there are important post-translational modifiers which could drive critical insights on thyroid cancer genetics. Results In this study, we have conducted a threshold analysis for varying methylation levels to identify whether setting a methylation level threshold increases the performance of functional enrichment. Moreover, in order to decide on best-performing analysis strategy, we have performed data integration analysis including comparison of 10 different analysis strategies. As a result, combining methylation with expression and using genes with more than 15% methylation change led to optimal detection rate of thyroid-cancer associated pathways in top 20 functional enrichment results. Furthermore, pooling the data from different experiments increased analysis confidence by improving the data range. Consequently, we have identified 207 transcription factors and 245 post-translational modifiers with more than 15% methylation change which may be important in understanding underlying mechanisms of thyroid cancer. Conclusion While only expression or only methylation information would not reveal both primary and secondary mechanisms involved in disease state, combining expression and methylation led to a better detection of thyroid cancer-related genes and pathways that are found in the recent literature. Moreover, focusing on genes that have certain level of methylation change improved the functional enrichment results, revealing the core pathways involved in disease development such as; endocytosis, apoptosis, glutamatergic synapse, MAPK, ErbB, TGF-beta and Toll-like receptor pathways. Overall, in addition to novel analysis framework, our study reveals important thyroid-cancer related mechanisms, secondary molecular alterations and contributes to better knowledge of thyroid cancer aetiology. PMID:26678064

Gene Set−Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer

PubMed Central

Chang, Chia-Ming; Chuang, Chi-Mu; Wang, Mong-Lien; Yang, Yi-Ping; Chuang, Jen-Hua; Yang, Ming-Jie; Yen, Ming-Shyen; Chiou, Shih-Hwa; Chang, Cheng-Chang

2016-01-01

Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis. PMID:27527159

Abnormal cardiac autonomic regulation in mice lacking ASIC3.

PubMed

Cheng, Ching-Feng; Kuo, Terry B J; Chen, Wei-Nan; Lin, Chao-Chieh; Chen, Chih-Cheng

2014-01-01

Integration of sympathetic and parasympathetic outflow is essential in maintaining normal cardiac autonomic function. Recent studies demonstrate that acid-sensing ion channel 3 (ASIC3) is a sensitive acid sensor for cardiac ischemia and prolonged mild acidification can open ASIC3 and evoke a sustained inward current that fires action potentials in cardiac sensory neurons. However, the physiological role of ASIC3 in cardiac autonomic regulation is not known. In this study, we elucidate the role of ASIC3 in cardiac autonomic function using Asic3(-/-) mice. Asic3(-/-) mice showed normal baseline heart rate and lower blood pressure as compared with their wild-type littermates. Heart rate variability analyses revealed imbalanced autonomic regulation, with decreased sympathetic function. Furthermore, Asic3(-/-) mice demonstrated a blunted response to isoproterenol-induced cardiac tachycardia and prolonged duration to recover to baseline heart rate. Moreover, quantitative RT-PCR analysis of gene expression in sensory ganglia and heart revealed that no gene compensation for muscarinic acetylcholines receptors and beta-adrenalin receptors were found in Asic3(-/-) mice. In summary, we unraveled an important role of ASIC3 in regulating cardiac autonomic function, whereby loss of ASIC3 alters the normal physiological response to ischemic stimuli, which reveals new implications for therapy in autonomic nervous system-related cardiovascular diseases.

Quantitative proteomic study of Aspergillus Fumigatus secretome revealed deamidation of secretory enzymes.

PubMed

Adav, Sunil S; Ravindran, Anita; Sze, Siu Kwan

2015-04-24

Aspergillus sp. plays an essential role in lignocellulosic biomass recycling and is also exploited as cell factories for the production of industrial enzymes. This study profiled the secretome of Aspergillus fumigatus when grown with cellulose, xylan and starch by high throughput quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ). Post translational modifications (PTMs) of proteins play a critical role in protein functions. However, our understanding of the PTMs in secretory proteins is limited. Here, we present the identification of PTMs such as deamidation of secreted proteins of A. fumigatus. This study quantified diverse groups of extracellular secreted enzymes and their functional classification revealed cellulases and glycoside hydrolases (32.9%), amylases (0.9%), hemicellulases (16.2%), lignin degrading enzymes (8.1%), peptidases and proteases (11.7%), chitinases, lipases and phosphatases (7.6%), and proteins with unknown function (22.5%). The comparison of quantitative iTRAQ results revealed that cellulose and xylan stimulates expression of specific cellulases and hemicellulases, and their abundance level as a function of substrate. In-depth data analysis revealed deamidation as a major PTM of key cellulose hydrolyzing enzymes like endoglucanases, cellobiohydrolases and glucosidases. Hemicellulose degrading endo-1,4-beta-xylanase, monosidases, xylosidases, lignin degrading laccase, isoamyl alcohol oxidase and oxidoreductases were also found to be deamidated. The filamentous fungi play an essential role in lignocellulosic biomass recycling and fungal strains belonging to Aspergillus were also exploited as cell factories for the production of organic acids, pharmaceuticals, and industrially important enzymes. In this study, extracellular proteins secreted by thermophilic A. fumigatus when grown with cellulose, xylan and starch were profiled using isobaric tags for relative and absolute quantification (iTRAQ) by adopting liquid chromatography tandem mass spectrometry. The comparison of quantitative iTRAQ results revealed that cellulose and xylan stimulate expression of specific cellulases and hemicellulases, and expression level as a function of substrate. Post translational modifications revealed deamidation of key cellulases including endoglucanases, cellobiohydrolases and glucosidases; and hemicellulases and lignin degrading enzymes. The knowledge on deamidated enzymes along with specific sites of modifications could be crucial information for further functional studies of these enzymes of A. fumigatus. Copyright © 2015 Elsevier B.V. All rights reserved.

Metal Transport across Biomembranes: Emerging Models for a Distinct Chemistry*

PubMed Central

Argüello, José M.; Raimunda, Daniel; González-Guerrero, Manuel

2012-01-01

Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models. PMID:22389499

Metal transport across biomembranes: emerging models for a distinct chemistry.

PubMed

Argüello, José M; Raimunda, Daniel; González-Guerrero, Manuel

2012-04-20

Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models.

Functional Comparison of Bacteria from the Human Gut and Closely Related Non-Gut Bacteria Reveals the Importance of Conjugation and a Paucity of Motility and Chemotaxis Functions in the Gut Environment.

PubMed

Dobrijevic, Dragana; Abraham, Anne-Laure; Jamet, Alexandre; Maguin, Emmanuelle; van de Guchte, Maarten

2016-01-01

The human GI tract is a complex and still poorly understood environment, inhabited by one of the densest microbial communities on earth. The gut microbiota is shaped by millennia of evolution to co-exist with the host in commensal or symbiotic relationships. Members of the gut microbiota perform specific molecular functions important in the human gut environment. This can be illustrated by the presence of a highly expanded repertoire of proteins involved in carbohydrate metabolism, in phase with the large diversity of polysaccharides originating from the diet or from the host itself that can be encountered in this environment. In order to identify other bacterial functions that are important in the human gut environment, we investigated the distribution of functional groups of proteins in a group of human gut bacteria and their close non-gut relatives. Complementary to earlier global comparisons between different ecosystems, this approach should allow a closer focus on a group of functions directly related to the gut environment while avoiding functions related to taxonomically divergent microbiota composition, which may or may not be relevant for gut homeostasis. We identified several functions that are overrepresented in the human gut bacteria which had not been recognized in a global approach. The observed under-representation of certain other functions may be equally important for gut homeostasis. Together, these analyses provide us with new information about this environment so critical to our health and well-being.

Functional Comparison of Bacteria from the Human Gut and Closely Related Non-Gut Bacteria Reveals the Importance of Conjugation and a Paucity of Motility and Chemotaxis Functions in the Gut Environment

PubMed Central

Dobrijevic, Dragana; Abraham, Anne-Laure; Jamet, Alexandre; Maguin, Emmanuelle; van de Guchte, Maarten

2016-01-01

The human GI tract is a complex and still poorly understood environment, inhabited by one of the densest microbial communities on earth. The gut microbiota is shaped by millennia of evolution to co-exist with the host in commensal or symbiotic relationships. Members of the gut microbiota perform specific molecular functions important in the human gut environment. This can be illustrated by the presence of a highly expanded repertoire of proteins involved in carbohydrate metabolism, in phase with the large diversity of polysaccharides originating from the diet or from the host itself that can be encountered in this environment. In order to identify other bacterial functions that are important in the human gut environment, we investigated the distribution of functional groups of proteins in a group of human gut bacteria and their close non-gut relatives. Complementary to earlier global comparisons between different ecosystems, this approach should allow a closer focus on a group of functions directly related to the gut environment while avoiding functions related to taxonomically divergent microbiota composition, which may or may not be relevant for gut homeostasis. We identified several functions that are overrepresented in the human gut bacteria which had not been recognized in a global approach. The observed under-representation of certain other functions may be equally important for gut homeostasis. Together, these analyses provide us with new information about this environment so critical to our health and well-being. PMID:27416027

Horizontal gene transfer in silkworm, Bombyx mori

PubMed Central

2011-01-01

Background The domesticated silkworm, Bombyx mori, is the model insect for the order Lepidoptera, has economically important values, and has gained some representative behavioral characteristics compared to its wild ancestor. The genome of B. mori has been fully sequenced while function analysis of BmChi-h and BmSuc1 genes revealed that horizontal gene transfer (HGT) maybe bestow a clear selective advantage to B. mori. However, the role of HGT in the evolutionary history of B. mori is largely unexplored. In this study, we compare the whole genome of B. mori with those of 382 prokaryotic and eukaryotic species to investigate the potential HGTs. Results Ten candidate HGT events were defined in B. mori by comprehensive sequence analysis using Maximum Likelihood and Bayesian method combining with EST checking. Phylogenetic analysis of the candidate HGT genes suggested that one HGT was plant-to- B. mori transfer while nine were bacteria-to- B. mori transfer. Furthermore, functional analysis based on expression, coexpression and related literature searching revealed that several HGT candidate genes have added important characters, such as resistance to pathogen, to B. mori. Conclusions Results from this study clearly demonstrated that HGTs play an important role in the evolution of B. mori although the number of HGT events in B. mori is in general smaller than those of microbes and other insects. In particular, interdomain HGTs in B. mori may give rise to functional, persistent, and possibly evolutionarily significant new genes. PMID:21595916

In Vivo Imaging of Flavoprotein Fluorescence During Hypoxia Reveals the Importance of Direct Arterial Oxygen Supply to Cerebral Cortex Tissue.

PubMed

Chisholm, K I; Ida, K K; Davies, A L; Papkovsky, D B; Singer, M; Dyson, A; Tachtsidis, I; Duchen, M R; Smith, K J

2016-01-01

Live imaging of mitochondrial function is crucial to understand the important role played by these organelles in a wide range of diseases. The mitochondrial redox potential is a particularly informative measure of mitochondrial function, and can be monitored using the endogenous green fluorescence of oxidized mitochondrial flavoproteins. Here, we have observed flavoprotein fluorescence in the exposed murine cerebral cortex in vivo using confocal imaging; the mitochondrial origin of the signal was confirmed using agents known to manipulate mitochondrial redox potential. The effects of cerebral oxygenation on flavoprotein fluorescence were determined by manipulating the inspired oxygen concentration. We report that flavoprotein fluorescence is sensitive to reductions in cortical oxygenation, such that reductions in inspired oxygen resulted in loss of flavoprotein fluorescence with the exception of a preserved 'halo' of signal in periarterial regions. The findings are consistent with reports that arteries play an important role in supplying oxygen directly to tissue in the cerebral cortex, maintaining mitochondrial function.

An exemplar-based approach to individualized parcellation reveals the need for sex specific functional networks

PubMed Central

Salehi, Mehraveh; Karbasi, Amin; Shen, Xilin; Scheinost, Dustin; Constable, R. Todd

2018-01-01

Recent work with functional connectivity data has led to significant progress in understanding the functional organization of the brain. While the majority of the literature has focused on group-level parcellation approaches, there is ample evidence that the brain varies in both structure and function across individuals. In this work, we introduce a parcellation technique that incorporates delineation of functional networks both at the individual- and group-level. The proposed technique deploys the notion of “submodularity” to jointly parcellate the cerebral cortex while establishing an inclusive correspondence between the individualized functional networks. Using this parcellation technique, we successfully established a cross-validated predictive model that predicts individuals’ sex, solely based on the parcellation schemes (i.e. the node-to-network assignment vectors). The sex prediction finding illustrates that individualized parcellation of functional networks can reveal subgroups in a population and suggests that the use of a global network parcellation may overlook fundamental differences in network organization. This is a particularly important point to consider in studies comparing patients versus controls or even patient subgroups. Network organization may differ between individuals and global configurations should not be assumed. This approach to the individualized study of functional organization in the brain has many implications for both neuroscience and clinical applications. PMID:28882628

Structural landscape of base pairs containing post-transcriptional modifications in RNA

PubMed Central

Seelam, Preethi P.; Sharma, Purshotam

2017-01-01

Base pairs involving post-transcriptionally modified nucleobases are believed to play important roles in a wide variety of functional RNAs. Here we present our attempts toward understanding the structural and functional role of naturally occurring modified base pairs using a combination of X-ray crystal structure database analysis, sequence analysis, and advanced quantum chemical methods. Our bioinformatics analysis reveals that despite their presence in all major secondary structural elements, modified base pairs are most prevalent in tRNA crystal structures and most commonly involve guanine or uridine modifications. Further, analysis of tRNA sequences reveals additional examples of modified base pairs at structurally conserved tRNA regions and highlights the conservation patterns of these base pairs in three domains of life. Comparison of structures and binding energies of modified base pairs with their unmodified counterparts, using quantum chemical methods, allowed us to classify the base modifications in terms of the nature of their electronic structure effects on base-pairing. Analysis of specific structural contexts of modified base pairs in RNA crystal structures revealed several interesting scenarios, including those at the tRNA:rRNA interface, antibiotic-binding sites on the ribosome, and the three-way junctions within tRNA. These scenarios, when analyzed in the context of available experimental data, allowed us to correlate the occurrence and strength of modified base pairs with their specific functional roles. Overall, our study highlights the structural importance of modified base pairs in RNA and points toward the need for greater appreciation of the role of modified bases and their interactions, in the context of many biological processes involving RNA. PMID:28341704

Exploring the evolutionary ecology of fungal endophyte in agricultural systems: using functional traits to reveal mechanisms in community processes

USDA-ARS?s Scientific Manuscript database

All plants, including crop species, harbor a community of fungal endophyte species, however, we know little about the biotic factors that are important in endophyte community assembly. We suggest that the most direct route to understanding the mechanisms underlying community assembly is through the...

IL-22 from T cells: better late than never.

PubMed

Honda, Kenya

2012-12-14

Interleukin-22 (IL-22) enhances mucosal barrier function and is important in antimicrobial host defense. In this issue of Immunity, Basu et al. (2012) reveal that Th22 cells are the critical adaptive source of IL-22 during late-phase infection by Citrobacter rodentium. Copyright © 2012 Elsevier Inc. All rights reserved.

Plants for Play: A Plant Selection Guide for Children's Outdoor Environments.

ERIC Educational Resources Information Center

Moore, Robin C.

This book presents guidelines in the design and management of children's landscapes and reveals the importance of plants as a resource for play and child development. It identifies plants by function, i.e., their sensory values, play values, food production, seasonal interest, shade quality, screens against natural barriers, wildlife enhancement,…

Multiple loss-of-function 5-O-Glucosyltransferase alleles revealed in Vitis vinifera, but not in other Vitis species

USDA-ARS?s Scientific Manuscript database

Anthocyanins in red grapes (Vitis genus) are important components of wine and beneficial to human health. These antioxidant compounds are present in two glycosylation states: monoglucoside (3-O-glucoside) and diglucoside (3, 5-di-O-glucoside). While monoglucoside anthocyanins are present in all pigm...

Molecular and functional characterization of Bemisia tabaci aquaporins reveals the water channel diversity of hemipteran insects

USDA-ARS?s Scientific Manuscript database

The Middle East-Asia Minor 1 (MEAM1) whitefly, Bemisia tabaci (Gennadius) is an economically important pest of food, fiber, and ornamental crops. This pest has evolved a number of adaptations to overcome physiological challenges, including 1) the ability to regulate osmotic stress between gut lumen ...

PhOBF1, a petunia OCS element binding factor, plays an important role in antiviral RNA silencing

USDA-ARS?s Scientific Manuscript database

Virus-induced gene silencing (VIGS) is a common strategy of reverse genetics for characterizing function of genes in plant. The detailed mechanism governing RNA silencing efficiency triggered by virus is largely unclear. Here, we revealed that a petunia (Petunia hybrida) ocs element binding factor, ...

Patterns of Children's Adrenocortical Reactivity to Interparental Conflict and Associations with Child Adjustment: A Growth Mixture Modeling Approach

ERIC Educational Resources Information Center

Koss, Kalsea J.; George, Melissa R. W.; Davies, Patrick T.; Cicchetti, Dante; Cummings, E. Mark; Sturge-Apple, Melissa L.

2013-01-01

Examining children's physiological functioning is an important direction for understanding the links between interparental conflict and child adjustment. Utilizing growth mixture modeling, the present study examined children's cortisol reactivity patterns in response to a marital dispute. Analyses revealed three different patterns of cortisol…

Characterization of WRKY transcription factors in Solanum lycopersicum reveals collinearity and their expression patterns under cold treatment.

PubMed

Chen, Lin; Yang, Yang; Liu, Can; Zheng, Yanyan; Xu, Mingshuang; Wu, Na; Sheng, Jiping; Shen, Lin

2015-08-28

WRKY transcription factors play an important role in cold defense of plants. However, little information is available about the cold-responsive WRKYs in tomato (Solanum lycopersicum). In the present study, a complete characterization of this gene family was described. Eighty WRKY genes in the tomato genome were identified. Almost all WRKY genes contain putative stress-responsive cis-elements in their promoter regions. Segmental duplications contributed significantly to the expansion of the SlWRKY gene family. Transcriptional analysis revealed notable differential expression in tomato tissues and expression patterns under cold stress, which indicated wide functional divergence in this family. Ten WRKYs in tomato were strongly induced more than 2-fold during cold stress. These genes represented candidate genes for future functional analysis of WRKYs involved in the cold-related signal pathways. Our data provide valuable information about tomato WRKY proteins and form a foundation for future studies of these proteins, especially for those that play an important role in response to cold stress. Copyright © 2015 Elsevier Inc. All rights reserved.

CD8 T cell memory: it takes all kinds

PubMed Central

Hamilton, Sara E.; Jameson, Stephen C.

2012-01-01

Understanding the mechanisms that regulate the differentiation and maintenance of CD8+ memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8+ memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8+ memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine design. Here we discuss how the diversity of the memory CD8+ T cell pool challenges the notion that “one size fits all” for pathogen control, and how distinct memory subsets may be suited for distinct aspects of protective immunity. PMID:23230436

Genetic regulation of salt stress tolerance revealed by RNA-Seq in cotton diploid wild species, Gossypium davidsonii

PubMed Central

Zhang, Feng; Zhu, Guozhong; Du, Lei; Shang, Xiaoguang; Cheng, Chaoze; Yang, Bing; Hu, Yan; Cai, Caiping; Guo, Wangzhen

2016-01-01

Cotton is an economically important crop throughout the world, and is a pioneer crop in salt stress tolerance research. Investigation of the genetic regulation of salinity tolerance will provide information for salt stress-resistant breeding. Here, we employed next-generation RNA-Seq technology to elucidate the salt-tolerant mechanisms in cotton using the diploid cotton species Gossypium davidsonii which has superior stress tolerance. A total of 4744 and 5337 differentially expressed genes (DEGs) were found to be involved in salt stress tolerance in roots and leaves, respectively. Gene function annotation elucidated salt overly sensitive (SOS) and reactive oxygen species (ROS) signaling pathways. Furthermore, we found that photosynthesis pathways and metabolism play important roles in ion homeostasis and oxidation balance. Moreover, our studies revealed that alternative splicing also contributes to salt-stress responses at the posttranscriptional level, implying its functional role in response to salinity stress. This study not only provides a valuable resource for understanding the genetic control of salt stress in cotton, but also lays a substantial foundation for the genetic improvement of crop resistance to salt stress. PMID:26838812

Genetic regulation of salt stress tolerance revealed by RNA-Seq in cotton diploid wild species, Gossypium davidsonii.

PubMed

Zhang, Feng; Zhu, Guozhong; Du, Lei; Shang, Xiaoguang; Cheng, Chaoze; Yang, Bing; Hu, Yan; Cai, Caiping; Guo, Wangzhen

2016-02-03

Cotton is an economically important crop throughout the world, and is a pioneer crop in salt stress tolerance research. Investigation of the genetic regulation of salinity tolerance will provide information for salt stress-resistant breeding. Here, we employed next-generation RNA-Seq technology to elucidate the salt-tolerant mechanisms in cotton using the diploid cotton species Gossypium davidsonii which has superior stress tolerance. A total of 4744 and 5337 differentially expressed genes (DEGs) were found to be involved in salt stress tolerance in roots and leaves, respectively. Gene function annotation elucidated salt overly sensitive (SOS) and reactive oxygen species (ROS) signaling pathways. Furthermore, we found that photosynthesis pathways and metabolism play important roles in ion homeostasis and oxidation balance. Moreover, our studies revealed that alternative splicing also contributes to salt-stress responses at the posttranscriptional level, implying its functional role in response to salinity stress. This study not only provides a valuable resource for understanding the genetic control of salt stress in cotton, but also lays a substantial foundation for the genetic improvement of crop resistance to salt stress.

Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis.

PubMed

Nandi, Sayan; Alviña, Karina; Lituma, Pablo J; Castillo, Pablo E; Hébert, Jean M

2018-01-15

Dentate granule cells (DGCs) play important roles in cognitive processes. Knowledge about how growth factors such as FGFs and neurotrophins contribute to the maturation and synaptogenesis of DGCs is limited. Here, using brain-specific and germline mouse mutants we show that a module of neurotrophin and FGF signaling, the FGF Receptor Substrate (FRS) family of intracellular adapters, FRS2 and FRS3, are together required for postnatal brain development. In the hippocampus, FRS promotes dentate gyrus morphogenesis and DGC maturation during developmental neurogenesis, similar to previously published functions for both neurotrophins and FGFs. Consistent with a role in DGC maturation, two-photon imaging revealed that Frs2,3-double mutants have reduced numbers of dendritic branches and spines in DGCs. Functional analysis further showed that double-mutant mice exhibit fewer excitatory synaptic inputs onto DGCs. These observations reveal roles for FRS adapters in DGC maturation and synaptogenesis and suggest that FRS proteins may act as an important node for FGF and neurotrophin signaling in postnatal hippocampal development. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

PubMed Central

Chan, John D.; Agbedanu, Prince N.; Grab, Thomas; Zamanian, Mostafa; Dosa, Peter I.; Day, Timothy A.; Marchant, Jonathan S.

2015-01-01

Abstract Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors. PMID:26367744

Transference and countertransference to medication and its implications for ego function.

PubMed

Marcus, Eric R

2007-01-01

Transference to medication can provide important information about specific ego dysfunction in sicker patients who often need medication. Whether positive or negative or both in content, the organization of the experience provides one example of the illness' effect on the patients' ego and can therefore be a specific diagnostic assessment strategy. Early resistances to medication may reveal the nature of resistances to the therapeutic alliance and to higher-level ego function. Understanding this can guide verbal and pharmacological interventions to strengthen ego function. Countertransference can similarly be helpful because it, too, can be a highly specific diagnostic indicator.

Image Analysis of DNA Fiber and Nucleus in Plants.

PubMed

Ohmido, Nobuko; Wako, Toshiyuki; Kato, Seiji; Fukui, Kiichi

2016-01-01

Advances in cytology have led to the application of a wide range of visualization methods in plant genome studies. Image analysis methods are indispensable tools where morphology, density, and color play important roles in the biological systems. Visualization and image analysis methods are useful techniques in the analyses of the detailed structure and function of extended DNA fibers (EDFs) and interphase nuclei. The EDF is the highest in the spatial resolving power to reveal genome structure and it can be used for physical mapping, especially for closely located genes and tandemly repeated sequences. One the other hand, analyzing nuclear DNA and proteins would reveal nuclear structure and functions. In this chapter, we describe the image analysis protocol for quantitatively analyzing different types of plant genome, EDFs and interphase nuclei.

Imaging episodic memory: implications for cognitive theories and phenomena.

PubMed

Nyberg, L

1999-01-01

Functional neuroimaging studies are beginning to identify neuroanatomical correlates of various cognitive functions. This paper presents results relevant to several theories and phenomena of episodic memory, including component processes of episodic retrieval, encoding specificity, inhibition, item versus source memory, encoding-retrieval overlap, and the picture-superiority effect. Overall, by revealing specific activation patterns, the results provide support for existing theoretical views and they add some unique information which may be important to consider in future attempts to develop cognitive theories of episodic memory.

[Factor structure of regional CBF and CMRglu values as a tool for the study of default mode of the brain].

PubMed

Kataev, G V; Korotkov, A D; Kireev, M V; Medvedev, S V

2013-01-01

In the present article it was shown that the functional connectivity of brain structures, revealed by factor analysis of resting PET CBF and rCMRglu data, is an adequate tool to study the default mode of the human brain. The identification of neuroanatomic systems of default mode (default mode network) during routine clinical PET investigations is important for further studying the functional organization of the normal brain and its reorganizations in pathological conditions.

Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain.

PubMed

Khacho, Mireille; Slack, Ruth S

2018-01-01

Mitochondria are classically known to be the cellular energy producers, but a renewed appreciation for these organelles has developed with the accumulating discoveries of additional functions. The importance of mitochondria within the brain has been long known, particularly given the high-energy demanding nature of neurons. The energy demands imposed by neurons require the well-orchestrated morphological adaptation and distribution of mitochondria. Recent studies now reveal the importance of mitochondrial dynamics not only in mature neurons but also during neural development, particularly during the process of neurogenesis and neural stem cell fate decisions. In this review, we will highlight the recent findings that illustrate the importance of mitochondrial dynamics in neurodevelopment and neural stem cell function. Developmental Dynamics 247:47-53, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

A Proteome-wide Fission Yeast Interactome Reveals Network Evolution Principles from Yeasts to Human.

PubMed

Vo, Tommy V; Das, Jishnu; Meyer, Michael J; Cordero, Nicolas A; Akturk, Nurten; Wei, Xiaomu; Fair, Benjamin J; Degatano, Andrew G; Fragoza, Robert; Liu, Lisa G; Matsuyama, Akihisa; Trickey, Michelle; Horibata, Sachi; Grimson, Andrew; Yamano, Hiroyuki; Yoshida, Minoru; Roth, Frederick P; Pleiss, Jeffrey A; Xia, Yu; Yu, Haiyuan

2016-01-14

Here, we present FissionNet, a proteome-wide binary protein interactome for S. pombe, comprising 2,278 high-quality interactions, of which ∼ 50% were previously not reported in any species. FissionNet unravels previously unreported interactions implicated in processes such as gene silencing and pre-mRNA splicing. We developed a rigorous network comparison framework that accounts for assay sensitivity and specificity, revealing extensive species-specific network rewiring between fission yeast, budding yeast, and human. Surprisingly, although genes are better conserved between the yeasts, S. pombe interactions are significantly better conserved in human than in S. cerevisiae. Our framework also reveals that different modes of gene duplication influence the extent to which paralogous proteins are functionally repurposed. Finally, cross-species interactome mapping demonstrates that coevolution of interacting proteins is remarkably prevalent, a result with important implications for studying human disease in model organisms. Overall, FissionNet is a valuable resource for understanding protein functions and their evolution. Copyright © 2016 Elsevier Inc. All rights reserved.

What have we learned about GPER function in physiology and disease from knockout mice?

PubMed Central

Prossnitz, Eric R.; Hathaway, Helen J.

2015-01-01

Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and patho-physiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also revealed roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer. PMID:26189910

The mentoring of male and female scientists during their doctoral studies

NASA Astrophysics Data System (ADS)

Filippelli, Laura Ann

The mentoring relationships of male and female scientists during their doctoral studies were examined. Male and female biologists, chemists, engineers and physicists were compared regarding the importance of doctoral students receiving career enhancing and psychosocial mentoring from their doctoral chairperson and student colleagues. Scientists' satisfaction with their chairperson and colleagues as providers of these mentoring functions was also investigated. In addition, scientists identified individuals other than their chairperson and colleagues who were positive influencers on their professional development as scientists and those who hindered their development. A reliable instrument, "The Survey of Accomplished Scientists' Doctoral Experiences," was developed to assess career enhancing and psychosocial mentoring of doctoral chairpersons and student colleagues based on the review of literature, interviews with scientists and two pilot studies. Surveys were mailed to a total of 400 men and women scientists with earned doctorates, of which 209 were completed and returned. The findings reveal that female scientists considered the doctoral chairperson furnishing career enhancing mentoring more important than did the men, while both were in accordance with the importance of them providing psychosocial mentoring. In addition, female scientists were not as satisfied as men with their chairperson providing most of the career enhancing and psychosocial mentoring functions. For doctoral student colleagues, female scientists, when compared to men, indicated that they considered student colleagues more important in providing career enhancing and psychosocial mentoring. However, male and female scientists were equally satisfied with their colleagues as providers of these mentoring functions. Lastly, the majority of male scientists indicated that professors served as a positive influencer, while women revealed that spouses and friends positively influenced their professional development as scientists. Several recommended changes in science departments are provided.

Trophic Mode-Dependent Proteomic Analysis Reveals Functional Significance of Light-Independent Chlorophyll Synthesis in Synechocystis sp. PCC 6803.

PubMed

Fang, Longfa; Ge, Haitao; Huang, Xiahe; Liu, Ye; Lu, Min; Wang, Jinlong; Chen, Weiyang; Xu, Wu; Wang, Yingchun

2017-01-09

The photosynthetic model organism Synechocystis sp. PCC 6803 can grow in different trophic modes, depending on the availability of light and exogenous organic carbon source. However, how the protein profile changes to facilitate the cells differentially propagate in different modes has not been comprehensively investigated. Using isobaric labeling-based quantitative proteomics, we simultaneously identified and quantified 45% Synechocystis proteome across four different trophic modes, i.e., autotrophic, heterotrophic, photoheterotrophic, and mixotrophic modes. Among the 155 proteins that are differentially expressed across four trophic modes, proteins involved in nitrogen assimilation and light-independent chlorophyll synthesis are dramatically upregulated in the mixotrophic mode, concomitant with a dramatic increase of P II phosphorylation that senses carbon and nitrogen assimilation status. Moreover, functional study using a mutant defective in light-independent chlorophyll synthesis revealed that this pathway is important for chlorophyll accumulation under a cycled light/dark illumination regime, a condition mimicking day/night cycles in certain natural habitats. Collectively, these results provide the most comprehensive information on trophic mode-dependent protein expression in cyanobacterium, and reveal the functional significance of light-independent chlorophyll synthesis in trophic growth. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

Role of executive functions in prospective memory in multiple sclerosis: Impact of the strength of cue-action association.

PubMed

Dagenais, Emmanuelle; Rouleau, Isabelle; Tremblay, Alexandra; Demers, Mélanie; Roger, Élaine; Jobin, Céline; Duquette, Pierre

2016-01-01

Patients diagnosed with multiple sclerosis (MS) often report prospective memory (PM) deficits. Although PM is important for daily functioning, it is not formally assessed in clinical practice. The aim of this study was to examine the role of executive functions in MS patients' PM revealed by the effect of strength of cue-action association on PM performance. Thirty-nine MS patients were compared to 18 healthy controls matched for age, gender, and education on a PM task modulating the strength of association between the cue and the intended action. Deficits in MS patients affecting both prospective and retrospective components of PM were confirmed using 2 × 2 × 2 mixed analyses of variance (ANOVAs). Among patients, multiple regression analyses revealed that the impairment was modulated by the efficiency of executive functions, whereas retrospective memory seemed to have little impact on PM performance, contrary to expectation. More specifically, results of 2 × 2 × 2 mixed-model analyses of covariance (ANCOVAs) showed that low-executive patients had more difficulty detecting and, especially, retrieving the appropriate action when the cue and the action were unrelated, whereas high-executive patients' performance seemed to be virtually unaffected by the cue-action association. Using an objective measure, these findings confirm the presence of PM deficits in MS. They also suggest that such deficits depend on executive functioning and can be reduced when automatic PM processes are engaged through semantic cue-action association. They underscore the importance of assessing PM in clinical settings through a cognitive evaluation and offer an interesting avenue for rehabilitation.

Magnetic exchange in {Gd(III)-radical} complexes: method assessment, mechanism of coupling and magneto-structural correlations.

PubMed

Gupta, Tulika; Rajeshkumar, Thayalan; Rajaraman, Gopalan

2014-07-28

Density functional studies have been performed on ten different {Gd(III)-radical} complexes exhibiting both ferro and antiferromagnetic exchange interaction with an aim to assess a suitable exchange-correlation functional within DFT formalism. This study has also been extended to probe the mechanism of magnetic coupling and to develop suitable magneto-structural correlations for this pair. Our method assessments reveal the following order of increasing accuracy for the evaluation of J values compared to experimental coupling constants: B(40HF)LYP < BHandHLYP < TPSSH < PW91 < PBE < BP86 < OLYP < BLYP < PBE0 < X3LYP < B3LYP < B2PLYP. Grimme's double-hybrid functional is found to be superior compared to other functionals tested and this is followed very closely by the conventional hybrid B3LYP functional. At the basis set front, our calculations reveal that the incorporation of relativistic effect is important in these calculations and the relativistically corrected effective core potential (ECP) basis set is found to yield better Js compared to other methods. The supposedly empty 5d/6s/6p orbitals of Gd(III) are found to play an important role in the mechanism of magnetic coupling and different contributions to the exchange terms are probed using Molecular Orbital (MO) and Natural Bond Orbital (NBO) analysis. Magneto-structural correlations for Gd-O distances, Gd-O-N angles and Gd-O-N-C dihedral angles are developed where the bond angles as well as dihedral angle parameters are found to dictate the sign and strength of the magnetic coupling in this series.

The cerebellum and cognition: evidence from functional imaging studies.

PubMed

Stoodley, Catherine J

2012-06-01

Evidence for a role of the human cerebellum in cognitive functions comes from anatomical, clinical and neuroimaging data. Functional neuroimaging reveals cerebellar activation during a variety of cognitive tasks, including language, visual-spatial, executive, and working memory processes. It is important to note that overt movement is not a prerequisite for cerebellar activation: the cerebellum is engaged during conditions which either control for motor output or do not involve motor responses. Resting-state functional connectivity data reveal that, in addition to networks underlying motor control, the cerebellum is part of "cognitive" networks with prefrontal and parietal association cortices. Consistent with these findings, regional differences in activation patterns within the cerebellum are evident depending on the task demands, suggesting that the cerebellum can be broadly divided into functional regions based on the patterns of anatomical connectivity between different regions of the cerebellum and sensorimotor and association areas of the cerebral cortex. However, the distinct contribution of the cerebellum to cognitive tasks is not clear. Here, the functional neuroimaging evidence for cerebellar involvement in cognitive functions is reviewed and related to hypotheses as to why the cerebellum is active during such tasks. Identifying the precise role of the cerebellum in cognition-as well as the mechanism by which the cerebellum modulates performance during a wide range of tasks-remains a challenge for future investigations.

Fungal proteomics: from identification to function.

PubMed

Doyle, Sean

2011-08-01

Some fungi cause disease in humans and plants, while others have demonstrable potential for the control of insect pests. In addition, fungi are also a rich reservoir of therapeutic metabolites and industrially useful enzymes. Detailed analysis of fungal biochemistry is now enabled by multiple technologies including protein mass spectrometry, genome and transcriptome sequencing and advances in bioinformatics. Yet, the assignment of function to fungal proteins, encoded either by in silico annotated, or unannotated genes, remains problematic. The purpose of this review is to describe the strategies used by many researchers to reveal protein function in fungi, and more importantly, to consolidate the nomenclature of 'unknown function protein' as opposed to 'hypothetical protein' - once any protein has been identified by protein mass spectrometry. A combination of approaches including comparative proteomics, pathogen-induced protein expression and immunoproteomics are outlined, which, when used in combination with a variety of other techniques (e.g. functional genomics, microarray analysis, immunochemical and infection model systems), appear to yield comprehensive and definitive information on protein function in fungi. The relative advantages of proteomic, as opposed to transcriptomic-only, analyses are also described. In the future, combined high-throughput, quantitative proteomics, allied to transcriptomic sequencing, are set to reveal much about protein function in fungi. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Systematic CRISPR-Cas9-Mediated Modifications of Plasmodium yoelii ApiAP2 Genes Reveal Functional Insights into Parasite Development

PubMed Central

Zhang, Cui; Li, Zhenkui; Cui, Huiting; Jiang, Yuanyuan; Yang, Zhenke; Wang, Xu; Gao, Han; Liu, Cong; Zhang, Shujia

2017-01-01

ABSTRACT Malaria parasites have a complex life cycle with multiple developmental stages in mosquito and vertebrate hosts, and different developmental stages express unique sets of genes. Unexpectedly, many transcription factors (TFs) commonly found in eukaryotic organisms are absent in malaria parasites; instead, a family of genes encoding proteins similar to the plant Apetala2 (ApiAP2) transcription factors is expanded in the parasites. Several malaria ApiAP2 genes have been shown to play a critical role in parasite development; however, the functions of the majority of the ApiAP2 genes remain to be elucidated. In particular, no study on the Plasmodium yoelii ApiAP2 (PyApiAP2) gene family has been reported so far. This study systematically investigated the functional roles of PyApiAP2 genes in parasite development. Twenty-four of the 26 PyApiAP2 genes were selected for disruption, and 12 were successfully knocked out using the clustered regularly interspaced short palindromic repeat–CRISPR-associated protein 9 (CRISPR-Cas9) method. The effects of gene knockout (KO) on parasite development in mouse and mosquito stages were evaluated. Ten of 12 successfully disrupted genes, including two genes that have not been functionally characterized in any Plasmodium species previously, were shown to be critical for P. yoelii development of sexual and mosquito stages. Additionally, seven of the genes were labeled for protein expression analysis, revealing important information supporting their functions. This study represents the first systematic functional characterization of the P. yoelii ApiAP2 gene family and discovers important insights on the roles of the ApiAP2 genes in parasite development. PMID:29233900

Uniform functional structure across spatial scales in an intertidal benthic assemblage.

PubMed

Barnes, R S K; Hamylton, Sarah

2015-05-01

To investigate the causes of the remarkable similarity of emergent assemblage properties that has been demonstrated across disparate intertidal seagrass sites and assemblages, this study examined whether their emergent functional-group metrics are scale related by testing the null hypothesis that functional diversity and the suite of dominant functional groups in seagrass-associated macrofauna are robust structural features of such assemblages and do not vary spatially across nested scales within a 0.4 ha area. This was carried out via a lattice of 64 spatially referenced stations. Although densities of individual components were patchily dispersed across the locality, rank orders of importance of the 14 functional groups present, their overall functional diversity and evenness, and the proportions of the total individuals contained within each showed, in contrast, statistically significant spatial uniformity, even at areal scales <2 m(2). Analysis of the proportional importance of the functional groups in their geospatial context also revealed weaker than expected levels of spatial autocorrelation, and then only at the smaller scales and amongst the most dominant groups, and only a small number of negative correlations occurred between the proportional importances of the individual groups. In effect, such patterning was a surface veneer overlying remarkable stability of assemblage functional composition across all spatial scales. Although assemblage species composition is known to be homogeneous in some soft-sediment marine systems over equivalent scales, this combination of patchy individual components yet basically constant functional-group structure seems as yet unreported. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cognitive functioning and everyday problem solving in older adults.

PubMed

Burton, Catherine L; Strauss, Esther; Hultsch, David F; Hunter, Michael A

2006-09-01

The relationship between cognitive functioning and a performance-based measure of everyday problem-solving, the Everyday Problems Test (EPT), thought to index instrumental activities of daily living (IADL), was examined in 291 community-dwelling non-demented older adults. Performance on the EPT was found to vary according to age, cognitive status, and education. Hierarchical regression analyses revealed that, after adjusting for demographic and health variables, measures of cognitive functioning accounted for 23.6% of the variance in EPT performance. In particular, measures of global cognitive status, cognitive decline, speed of processing, executive functioning, episodic memory, and verbal ability were significant predictors of EPT performance. These findings suggest that cognitive functioning along with demographic variables are important determinants of everyday problem-solving.

Molecular characterization, tissue distribution and expression analysis of TRIM25 in Gallus gallus domesticus.

PubMed

Feng, Ze-Qing; Cheng, Yang; Yang, Hui-Ling; Zhu, Qing; Yu, Dandan; Liu, Yi-Ping

2015-04-25

TRIM25, a member of the tripartite motif-containing (TRIM) family of proteins, plays an important role in cell proliferation, protein modification, and the RIG-I-mediated antiviral signaling pathway. However, relatively few studies have investigated the molecular characterization, tissue distribution, and potential function of TRIM25 in chickens. In this study, we cloned the full-length cDNA of chicken TRIM25 that is composed of 2706 bp. Sequence analyses revealed that TRIM25 contains a 1902-bp open-reading frame that probably encodes a 633-amino acid protein. Multiple comparisons with deduced amino acid sequences revealed that the RING finger and B30.2 domains of chicken TRIM25 share a high sequence similarity with human and murine TRIM25, indicating that these domains are critical for the function of chicken TRIM25. qPCR assays revealed that TRIM25 is highly expressed in the spleen, thymus and lungs in chickens. Furthermore, we observed that TRIM25 expression was significantly upregulated both in vitro and in vivo following infection with Newcastle disease virus. TRIM25 expression was also significantly upregulated in chicken embryo fibroblasts upon stimulation with poly(I:C) or poly(dA:dT). Taken together, these findings suggest that TRIM25 plays an important role in antiviral signaling pathways in chickens. Copyright © 2015 Elsevier B.V. All rights reserved.

Runx2 contributes to the regenerative potential of the mammary epithelium.

PubMed

Ferrari, Nicola; Riggio, Alessandra I; Mason, Susan; McDonald, Laura; King, Ayala; Higgins, Theresa; Rosewell, Ian; Neil, James C; Smalley, Matthew J; Sansom, Owen J; Morris, Joanna; Cameron, Ewan R; Blyth, Karen

2015-10-22

Although best known for its role in bone development and associated structures the transcription factor RUNX2 is expressed in a wide range of lineages, including those of the mammary gland. Previous studies have indicated that Runx2 can regulate aspects of mammary cell function and influence the properties of cancer cells. In this study we investigate the role of Runx2 in the mammary stem/progenitor population and its relationship with WNT signalling. Results show that RUNX2 protein is differentially expressed throughout embryonic and adult development of the murine mammary gland with high levels of expression in mammary stem-cell enriched cultures. Importantly, functional analysis reveals a role for Runx2 in mammary stem/progenitor cell function in in vitro and in vivo regenerative assays. Furthermore, RUNX2 appears to be associated with WNT signalling in the mammary epithelium and is specifically upregulated in mouse models of WNT-driven breast cancer. Overall our studies reveal a novel function for Runx2 in regulating mammary epithelial cell regenerative potential, possibly acting as a downstream target of WNT signalling.

Runx2 contributes to the regenerative potential of the mammary epithelium

PubMed Central

Ferrari, Nicola; Riggio, Alessandra I.; Mason, Susan; McDonald, Laura; King, Ayala; Higgins, Theresa; Rosewell, Ian; Neil, James C.; Smalley, Matthew J.; Sansom, Owen J.; Morris, Joanna; Cameron, Ewan R.; Blyth, Karen

2015-01-01

Although best known for its role in bone development and associated structures the transcription factor RUNX2 is expressed in a wide range of lineages, including those of the mammary gland. Previous studies have indicated that Runx2 can regulate aspects of mammary cell function and influence the properties of cancer cells. In this study we investigate the role of Runx2 in the mammary stem/progenitor population and its relationship with WNT signalling. Results show that RUNX2 protein is differentially expressed throughout embryonic and adult development of the murine mammary gland with high levels of expression in mammary stem-cell enriched cultures. Importantly, functional analysis reveals a role for Runx2 in mammary stem/progenitor cell function in in vitro and in vivo regenerative assays. Furthermore, RUNX2 appears to be associated with WNT signalling in the mammary epithelium and is specifically upregulated in mouse models of WNT-driven breast cancer. Overall our studies reveal a novel function for Runx2 in regulating mammary epithelial cell regenerative potential, possibly acting as a downstream target of WNT signalling. PMID:26489514

Informatic and genomic analysis of melanocyte cDNA libraries as a resource for the study of melanocyte development and function.

PubMed

Baxter, Laura L; Hsu, Benjamin J; Umayam, Lowell; Wolfsberg, Tyra G; Larson, Denise M; Frith, Martin C; Kawai, Jun; Hayashizaki, Yoshihide; Carninci, Piero; Pavan, William J

2007-06-01

As part of the RIKEN mouse encyclopedia project, two cDNA libraries were prepared from melanocyte-derived cell lines, using techniques of full-length clone selection and subtraction/normalization to enrich for rare transcripts. End sequencing showed that these libraries display over 83% complete coding sequence at the 5' end and 96-97% complete coding sequence at the 3' end. Evaluation of the libraries, derived from B16F10Y tumor cells and melan-c cells, revealed that they contain clones for a majority of the genes previously demonstrated to function in melanocyte biology. Analysis of genomic locations for transcripts revealed that the distribution of melanocyte genes is non-random throughout the genome. Three genomic regions identified that showed significant clustering of melanocyte-expressed genes contain one or more genes previously shown to regulate melanocyte development or function. A catalog of genes expressed in these libraries is presented, providing a valuable resource of cDNA clones and sequence information that can be used for identification of new genes important for melanocyte development, function, and disease.

AIRE is a critical spindle-associated protein in embryonic stem cells

PubMed Central

Gu, Bin; Lambert, Jean-Philippe; Cockburn, Katie; Gingras, Anne-Claude; Rossant, Janet

2017-01-01

Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells. We also identified the c-terminal LESLL motif as a critical motif for AIRE’s mitotic function. Combined maternal and zygotic knockout further revealed Aire’s critical functions for spindle assembly in preimplantation embryos. These results uncovered a previously unappreciated function for Aire and provide new insights into the biology of stem cell proliferation and potential new angles to understand fertility defects in humans carrying Aire mutations. DOI: http://dx.doi.org/10.7554/eLife.28131.001 PMID:28742026

Structural And Functional Studies of ALIX Interactions With YPXnL Late Domains of HIV-1 And EIAV

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhai, Q.; Fisher, R.D.; Chung, H.-Y.

2009-05-28

Retrovirus budding requires short peptide motifs (late domains) located within the viral Gag protein that function by recruiting cellular factors. The YPX{sub n}L late domains of HIV and other lentiviruses recruit the protein ALIX (also known as AIP1), which also functions in vesicle formation at the multivesicular body and in the abscission stage of cytokinesis. Here, we report the crystal structures of ALIX in complex with the YPX{sub n}L late domains from HIV-1 and EIAV. The two distinct late domains bind at the same site on the ALIX V domain but adopt different conformations that allow them to make equivalentmore » contacts. Binding studies and functional assays verified the importance of key interface residues and revealed that binding affinities are tuned by context-dependent effects. These results reveal how YPX{sub n}L late domains recruit ALIX to facilitate virus budding and how ALIX can bind YPX{sub n}L sequences with both n = 1 and n = 3.« less

The structure of human SFPQ reveals a coiled-coil mediated polymer essential for functional aggregation in gene regulation

PubMed Central

Lee, Mihwa; Sadowska, Agata; Bekere, Indra; Ho, Diwei; Gully, Benjamin S.; Lu, Yanling; Iyer, K. Swaminathan; Trewhella, Jill; Fox, Archa H.; Bond, Charles S.

2015-01-01

SFPQ, (a.k.a. PSF), is a human tumor suppressor protein that regulates many important functions in the cell nucleus including coordination of long non-coding RNA molecules into nuclear bodies. Here we describe the first crystal structures of Splicing Factor Proline and Glutamine Rich (SFPQ), revealing structural similarity to the related PSPC1/NONO heterodimer and a strikingly extended structure (over 265 Å long) formed by an unusual anti-parallel coiled-coil that results in an infinite linear polymer of SFPQ dimers within the crystals. Small-angle X-ray scattering and transmission electron microscopy experiments show that polymerization is reversible in solution and can be templated by DNA. We demonstrate that the ability to polymerize is essential for the cellular functions of SFPQ: disruptive mutation of the coiled-coil interaction motif results in SFPQ mislocalization, reduced formation of nuclear bodies, abrogated molecular interactions and deficient transcriptional regulation. The coiled-coil interaction motif thus provides a molecular explanation for the functional aggregation of SFPQ that directs its role in regulating many aspects of cellular nucleic acid metabolism. PMID:25765647

Segregated Fronto-Cerebellar Circuits Revealed by Intrinsic Functional Connectivity

PubMed Central

Buckner, Randy L.

2009-01-01

Multiple, segregated fronto-cerebellar circuits have been characterized in nonhuman primates using transneuronal tracing techniques including those that target prefrontal areas. Here, we used functional connectivity MRI (fcMRI) in humans (n = 40) to identify 4 topographically distinct fronto-cerebellar circuits that target 1) motor cortex, 2) dorsolateral prefrontal cortex, 3) medial prefrontal cortex, and 4) anterior prefrontal cortex. All 4 circuits were replicated and dissociated in an independent data set (n = 40). Direct comparison of right- and left-seeded frontal regions revealed contralateral lateralization in the cerebellum for each of the segregated circuits. The presence of circuits that involve prefrontal regions confirms that the cerebellum participates in networks important to cognition including a specific fronto-cerebellar circuit that interacts with the default network. Overall, the extent of the cerebellum associated with prefrontal cortex included a large portion of the posterior hemispheres consistent with a prominent role of the cerebellum in nonmotor functions. We conclude by providing a provisional map of the topography of the cerebellum based on functional correlations with the frontal cortex. PMID:19592571

The R-spondin family of proteins: emerging regulators of WNT signaling

PubMed Central

Jin, Yong-Ri; Yoon, Jeong Kyo

2012-01-01

Recently, the R-spondin (RSPO) family of proteins has emerged as important regulators of WNT signaling. Considering the wide spectrum of WNT signaling functions in normal biological processes and disease conditions, there has been a significantly growing interest in understanding the functional roles of RSPOs in multiple biological processes and determining the molecular mechanisms by which RSPOs regulate the WNT signaling pathway. Recent advances in the RSPO research field revealed some of the in vivo functions of RSPOs and provided new information regarding the mechanistic roles of RSPO activity in regulation of WNT signaling. Herein, we review recent progress in RSPO research with an emphasis on signaling mechanisms and biological functions. PMID:22982762

Recent Achievement in Gene Cloning and Functional Genomics in Soybean

PubMed Central

Zhai, Hong; Lü, Shixiang; Wu, Hongyan; Zhang, Yupeng

2013-01-01

Soybean is a model plant for photoperiodism as well as for symbiotic nitrogen fixation. However, a rather low efficiency in soybean transformation hampers functional analysis of genes isolated from soybean. In comparison, rapid development and progress in flowering time and photoperiodic response have been achieved in Arabidopsis and rice. As the soybean genomic information has been released since 2008, gene cloning and functional genomic studies have been revived as indicated by successfully characterizing genes involved in maturity and nematode resistance. Here, we review some major achievements in the cloning of some important genes and some specific features at genetic or genomic levels revealed by the analysis of functional genomics of soybean. PMID:24311973

Analysis of Tryptophan Residues in the Staphylococcal Multidrug Transporter QacA Reveals Long-Distance Functional Associations of Residues on Opposite Sides of the Membrane▿

PubMed Central

Hassan, Karl A.; Souhani, Talal; Skurray, Ronald A.; Brown, Melissa H.

2008-01-01

Tryptophan residues can possess a multitude of functions within a multidrug transport protein, e.g., mediating interactions with substrates or distal parts of the protein, or fulfilling a structural requirement, such as guiding the depth of membrane insertion. In this study, the nine tryptophan residues of the staphylococcal QacA multidrug efflux protein were individually mutated to alanine and phenylalanine, and the functional consequences of these changes were determined. Phenylalanine substitutions for each tryptophan residue were functionally tolerated. However, alanine modifications revealed an important functional role for three tryptophan residues, W58, W149, and W173, each of which is well conserved among QacA-related transport proteins in the major facilitator superfamily. The most functionally compromising mutation, an alanine substitution for W58, likely to be located at the extracellular interface of transmembrane segment 2, abolished all detectable QacA-mediated resistance and transport function. Second-site suppressor analyses identified several mutations that rescued the function of the W58A QacA mutant. Remarkably, all of these suppressor mutations were shown to be located in cytoplasmic loops between transmembrane helices 2 and 3 or 12 and 13, demonstrating novel functional associations between amino acid positions on opposite sides of the membrane and in distal N- and C-terminal regions of the QacA protein. PMID:18223078

Abnormal prefrontal cortex resting state functional connectivity and severity of internet gaming disorder.

PubMed

Jin, Chenwang; Zhang, Ting; Cai, Chenxi; Bi, Yanzhi; Li, Yangding; Yu, Dahua; Zhang, Ming; Yuan, Kai

2016-09-01

Internet Gaming Disorder (IGD) among adolescents has become an important public concern and gained more and more attention internationally. Recent studies focused on IGD and revealed brain abnormalities in the IGD group, especially the prefrontal cortex (PFC). However, the role of PFC-striatal circuits in pathology of IGD remains unknown. Twenty-five adolescents with IGD and 21 age- and gender-matched healthy controls were recruited in our study. Voxel-based morphometric (VBM) and functional connectivity analysis were employed to investigate the abnormal structural and resting-state properties of several frontal regions in individuals with online gaming addiction. Relative to healthy comparison subjects, IGD subjects showed significant decreased gray matter volume in PFC regions including the bilateral dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and the right supplementary motor area (SMA) after controlling for age and gender effects. We chose these regions as the seeding areas for the resting-state analysis and found that IGD subjects showed decreased functional connectivity between several cortical regions and our seeds, including the insula, and temporal and occipital cortices. Moreover, significant decreased functional connectivity between some important subcortical regions, i.e., dorsal striatum, pallidum, and thalamus, and our seeds were found in the IGD group and some of those changes were associated with the severity of IGD. Our results revealed the involvement of several PFC regions and related PFC-striatal circuits in the process of IGD and suggested IGD may share similar neural mechanisms with substance dependence at the circuit level.

Asy2/Mer2: an evolutionarily conserved mediator of meiotic recombination, pairing, and global chromosome compaction

PubMed Central

Tessé, Sophie; Bourbon, Henri-Marc; Debuchy, Robert; Budin, Karine; Dubois, Emeline; Liangran, Zhang; Antoine, Romain; Piolot, Tristan; Kleckner, Nancy; Zickler, Denise; Espagne, Eric

2017-01-01

Meiosis is the cellular program by which a diploid cell gives rise to haploid gametes for sexual reproduction. Meiotic progression depends on tight physical and functional coupling of recombination steps at the DNA level with specific organizational features of meiotic-prophase chromosomes. The present study reveals that every step of this coupling is mediated by a single molecule: Asy2/Mer2. We show that Mer2, identified so far only in budding and fission yeasts, is in fact evolutionarily conserved from fungi (Mer2/Rec15/Asy2/Bad42) to plants (PRD3/PAIR1) and mammals (IHO1). In yeasts, Mer2 mediates assembly of recombination–initiation complexes and double-strand breaks (DSBs). This role is conserved in the fungus Sordaria. However, functional analysis of 13 mer2 mutants and successive localization of Mer2 to axis, synaptonemal complex (SC), and chromatin revealed, in addition, three further important functions. First, after DSB formation, Mer2 is required for pairing by mediating homolog spatial juxtaposition, with implications for crossover (CO) patterning/interference. Second, Mer2 participates in the transfer/maintenance and release of recombination complexes to/from the SC central region. Third, after completion of recombination, potentially dependent on SUMOylation, Mer2 mediates global chromosome compaction and post-recombination chiasma development. Thus, beyond its role as a recombinosome–axis/SC linker molecule, Mer2 has important functions in relation to basic chromosome structure. PMID:29021238

TAM Receptor Signaling in Immune Homeostasis

PubMed Central

Rothlin, Carla V.; Carrera-Silva, Eugenio A.; Bosurgi, Lidia; Ghosh, Sourav

2015-01-01

The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease. PMID:25594431

Understanding subcellular function on the nanometer scale in real time: Single-molecule imaging in living bacteria

NASA Astrophysics Data System (ADS)

Biteen, Julie

It has long been recognized that microorganisms play a central role in our lives. By beating the diffraction limit that restricts traditional light microscopy, single-molecule fluorescence imaging is a precise, noninvasive way to sensitively probe position and dynamics, even in living cells. We are pioneering this super-resolution imaging method for unraveling important biological processes in live bacteria, and I will discuss how we infer function from subcellular dynamics (Tuson and Biteen, Analytical Chemistry 2015). In particular, we have understood the mechanism of membrane-bound transcription regulation in the pathogenic Vibrio cholerae, revealed an intimate and dynamic coupling between DNA mismatch recognition and DNA replication, and measured starch utilization in an important member of the human gut microbiome.

Ahr function in lymphocytes: emerging concepts

PubMed Central

Zhou, Liang

2015-01-01

The aryl hydrocarbon receptor (Ahr) is an important regulator of the development and function of both innate and adaptive immune cells through roles associated with Ahr's ability to respond to cellular and dietary ligands. Recent findings have revealed tissue and context-specific functions for Ahr in both homeostasis and in during an immune response. I review these findings here, and integrate them into the current understanding of the mechanisms that regulate Ahr transcription and function. I propose a conceptual framework in which Ahr function is determined by three factors: the amount of Ahr in any given cell, the abundance and potency of Ahr ligands within certain tissues, and the tissue microenvironment wherein Ahr+ cells reside. This complexity emphasizes the necessity cell-type specific genetic approaches towards the study of Ahr function. PMID:26700314

Let thy left brain know what thy right brain doeth: Inter-hemispheric compensation of functional deficits after brain damage.

PubMed

Bartolomeo, Paolo; Thiebaut de Schotten, Michel

2016-12-01

Recent evidence revealed the importance of inter-hemispheric communication for the compensation of functional deficits after brain damage. This review summarises the biological consequences observed using histology as well as the longitudinal findings measured with magnetic resonance imaging methods in brain damaged animals and patients. In particular, we discuss the impact of post-stroke brain hyperactivity on functional recovery in relation to time. The reviewed evidence also suggests that the proportion of the preserved functional network both in the lesioned and in the intact hemispheres, rather than the simple lesion location, determines the extent of functional recovery. Hence, future research exploring longitudinal changes in patients with brain damage may unveil potential biomarkers underlying functional recovery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Functional and mechanistic diversity of distal transcription enhancers

PubMed Central

Bulger, Michael; Groudine, Mark

2013-01-01

Biological differences among metazoans, and between cell types in a given organism, arise in large part due to differences in gene expression patterns. The sequencing of multiple metazoan genomes, coupled with recent advances in genome-wide analysis of histone modifications and transcription factor binding, has revealed that among regulatory DNA sequences, gene-distal enhancers appear to exhibit the greatest diversity and cell-type specificity. Moreover, such elements are emerging as important targets for mutations that can give rise to disease and to genetic variability that underlies evolutionary change. Studies of long-range interactions between distal genomic sequences in the nucleus indicate that enhancers are often important determinants of nuclear organization, contributing to a general model for enhancer function that involves direct enhancer-promoter contact. In a number of systems, however, mechanisms for enhancer function are emerging that do not fit solely within such a model, suggesting that enhancers as a class of DNA regulatory element may be functionally and mechanistically diverse. PMID:21295696

Immune function in arctic mammals: Natural killer (NK) cell-like activity in polar bear, muskox and reindeer.

PubMed

Desforges, Jean-Pierre; Jasperse, Lindsay; Jensen, Trine Hammer; Grøndahl, Carsten; Bertelsen, Mads F; Guise, Sylvain De; Sonne, Christian; Dietz, Rune; Levin, Milton

2018-01-01

Natural killer (NK) cells are a vital part of the rapid and non-specific immune defense against invading pathogens and tumor cells. This study evaluated NK cell-like activity by flow cytometry for the first time in three ecologically and culturally important Arctic mammal species: polar bear (Ursus maritimus), muskox (Ovibos moschatus) and reindeer (Rangifer tarandus). NK cell-like activity for all three species was most effective against the mouse lymphoma cell line YAC-1, compared to the human leukemia cell line K562; NK cell response displayed the characteristic increase in cytotoxic activity when the effector:target cell ratio increased. Comparing NK activity between fresh and cryopreserved mouse lymphocytes revealed little to no difference in function, highlighting the applicability of cryopreserving cells in field studies. The evaluation of this important innate immune function in Arctic mammals can contribute to future population health assessments, especially as pollution-induced suppression of immune function may increase infectious disease susceptibility. Copyright © 2017 Elsevier B.V. All rights reserved.

The bornavirus-derived human protein EBLN1 promotes efficient cell cycle transit, microtubule organisation and genome stability.

PubMed

Myers, Katie N; Barone, Giancarlo; Ganesh, Anil; Staples, Christopher J; Howard, Anna E; Beveridge, Ryan D; Maslen, Sarah; Skehel, J Mark; Collis, Spencer J

2016-10-14

It was recently discovered that vertebrate genomes contain multiple endogenised nucleotide sequences derived from the non-retroviral RNA bornavirus. Strikingly, some of these elements have been evolutionary maintained as open reading frames in host genomes for over 40 million years, suggesting that some endogenised bornavirus-derived elements (EBL) might encode functional proteins. EBLN1 is one such element established through endogenisation of the bornavirus N gene (BDV N). Here, we functionally characterise human EBLN1 as a novel regulator of genome stability. Cells depleted of human EBLN1 accumulate DNA damage both under non-stressed conditions and following exogenously induced DNA damage. EBLN1-depleted cells also exhibit cell cycle abnormalities and defects in microtubule organisation as well as premature centrosome splitting, which we attribute in part, to improper localisation of the nuclear envelope protein TPR. Our data therefore reveal that human EBLN1 possesses important cellular functions within human cells, and suggest that other EBLs present within vertebrate genomes may also possess important cellular functions.

Cis-dicarbonyl binding at cobalt and iron porphyrins with saddle-shape conformation.

PubMed

Seufert, Knud; Bocquet, Marie-Laure; Auwärter, Willi; Weber-Bargioni, Alexander; Reichert, Joachim; Lorente, Nicolás; Barth, Johannes V

2011-02-01

Diatomic molecules attached to complexed iron or cobalt centres are important in many biological processes. In natural systems, metallotetrapyrrole units carry respiratory gases or provide sensing and catalytic functions. Conceiving synthetic model systems strongly helps to determine the pertinent chemical foundations for such processes, with recent work highlighting the importance of the prosthetic groups' conformational flexibility as an intricate variable affecting their functional properties. Here, we present simple model systems to investigate, at the single molecule level, the interaction of carbon monoxide with saddle-shaped iron- and cobalt-porphyrin conformers, which have been stabilized as two-dimensional arrays on well-defined surfaces. Using scanning tunnelling microscopy we identified a novel bonding scheme expressed in tilted monocarbonyl and cis-dicarbonyl configurations at the functional metal-macrocycle unit. Modelling with density functional theory revealed that the weakly bonded diatomic carbonyl adduct can effectively bridge specific pyrrole groups with the metal atom as a result of the pronounced saddle-shape conformation of the porphyrin cage.

INHIBITION OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION BY PERFLUORINATED COMPOUNDS IN RAT LIVER AND DOLPHIN KIDNEY EPITHELIAL CELL LINES IN VITRO AND SPRAGUE-DAWLEY RATS IN VIVO

EPA Science Inventory

Abstract

Gap Junctional Intercellular Communication (GJIC) is the major pathway of intercellular signal transduction, and is, thus, important for normal cell growth and function. Recent studies have revealed a global distribution of some perfluorinated organic compounds e...

Functional analyses of cotton (Gossypium hirsutum L.) immature fiber (im) mutant reveal that fiber cell wall development is associated with sensitivity to stress.

USDA-ARS?s Scientific Manuscript database

Background: Cotton fiber maturity refers the degree of fiber cell wall development and is an important factor for determining commercial value of cotton. The molecular mechanism regulating the fiber cell wall development has not been well characterized. Microscopic image analysis of the cross-sect...

Genome-wide study of KNOX regulatory network reveals brassinosteroid catabolic genes important for shoot meristem function in rice

USDA-ARS?s Scientific Manuscript database

In flowering plants, knotted1-like homeobox (KNOX) transcription factors play crucial roles in establishment and maintenance of the shoot apical meristem (SAM), from which aerial organs such as leaves, stems, and flowers initiate. We report that a rice (Oryza sativa) KNOX gene Oryza sativa homeobox1...

Structural, Functional, and Genetic Analysis of Sorangicin Inhibition of Bacterial RNA Polymerase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campbell,E.; Pavlova, O.; Zenkin, N.

2005-01-01

A combined structural, functional, and genetic approach was used to investigate inhibition of bacterial RNA polymerase (RNAP) by sorangicin (Sor), a macrolide polyether antibiotic. Sor lacks chemical and structural similarity to the ansamycin rifampicin (Rif), an RNAP inhibitor widely used to treat tuberculosis. Nevertheless, structural analysis revealed Sor binds in the same RNAP {beta} subunit pocket as Rif, with almost complete overlap of RNAP binding determinants, and functional analysis revealed that both antibiotics inhibit transcription by directly blocking the path of the elongating transcript at a length of 2-3 nucleotides. Genetic analysis indicates that Rif binding is extremely sensitive tomore » mutations expected to change the shape of the antibiotic binding pocket, while Sor is not. We suggest that conformational flexibility of Sor, in contrast to the rigid conformation of Rif, allows Sor to adapt to changes in the binding pocket. This has important implications for drug design against rapidly mutating targets.« less

Molecular and cellular organization of taste neurons in adult Drosophila pharynx

PubMed Central

Chen, Yu-Chieh (David); Dahanukar, Anupama

2017-01-01

SUMMARY The Drosophila pharyngeal taste organs are poorly characterized despite their location at important sites for monitoring food quality. Functional analysis of pharyngeal neurons has been hindered by the paucity of molecular tools to manipulate them, as well as their relative inaccessibility for neurophysiological investigations. Here, we generate receptor-to-neuron maps of all three pharyngeal taste organs by performing a comprehensive chemoreceptor-GAL4/LexA expression analysis. The organization of pharyngeal neurons reveals similarities and distinctions in receptor repertoires and neuronal groupings compared to external taste neurons. We validate the mapping results by pinpointing a single pharyngeal neuron required for feeding avoidance of L-canavanine. Inducible activation of pharyngeal taste neurons reveals functional differences between external and internal taste neurons and functional subdivision within pharyngeal sweet neurons. Our results provide road maps of pharyngeal taste organs in an insect model system for probing the role of these understudied neurons in controlling feeding behaviors. PMID:29212040

ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae.

PubMed

Elefteriou, Florent; Benson, M Douglas; Sowa, Hideaki; Starbuck, Michael; Liu, Xiuyun; Ron, David; Parada, Luis F; Karsenty, Gerard

2006-12-01

The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1(ob)(-/-) mice without affecting other organ weight, while a high-protein diet overcame Atf4(-/-) and Rsk2(-/-) mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.

Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients

PubMed Central

Melber, Andrew; Na, Un; Vashisht, Ajay; Weiler, Benjamin D; Lill, Roland; Wohlschlegel, James A; Winge, Dennis R

2016-01-01

Iron-sulfur (Fe-S) clusters are essential for many cellular processes, ranging from aerobic respiration, metabolite biosynthesis, ribosome assembly and DNA repair. Mutations in NFU1 and BOLA3 have been linked to genetic diseases with defects in mitochondrial Fe-S centers. Through genetic studies in yeast, we demonstrate that Nfu1 functions in a late step of [4Fe-4S] cluster biogenesis that is of heightened importance during oxidative metabolism. Proteomic studies revealed Nfu1 physical interacts with components of the ISA [4Fe-4S] assembly complex and client proteins that need [4Fe-4S] clusters to function. Additional studies focused on the mitochondrial BolA proteins, Bol1 and Bol3 (yeast homolog to human BOLA3), revealing that Bol1 functions earlier in Fe-S biogenesis with the monothiol glutaredoxin, Grx5, and Bol3 functions late with Nfu1. Given these observations, we propose that Nfu1, assisted by Bol3, functions to facilitate Fe-S transfer from the biosynthetic apparatus to the client proteins preventing oxidative damage to [4Fe-4S] clusters. DOI: http://dx.doi.org/10.7554/eLife.15991.001 PMID:27532773

Same pattern, different mechanism: Locking onto the role of key species in seafloor ecosystem process

PubMed Central

Woodin, Sarah Ann; Volkenborn, Nils; Pilditch, Conrad A.; Lohrer, Andrew M.; Wethey, David S.; Hewitt, Judi E.; Thrush, Simon F.

2016-01-01

Seafloor biodiversity is a key mediator of ecosystem functioning, but its role is often excluded from global budgets or simplified to black boxes in models. New techniques allow quantification of the behavior of animals living below the sediment surface and assessment of the ecosystem consequences of complex interactions, yielding a better understanding of the role of seafloor animals in affecting key processes like primary productivity. Combining predictions based on natural history, behavior of key benthic species and environmental context allow assessment of differences in functioning and process, even when the measured ecosystem property in different systems is similar. Data from three sedimentary systems in New Zealand illustrate this. Analysis of the behaviors of the infaunal ecosystem engineers in each system revealed three very different mechanisms driving ecosystem function: density and excretion, sediment turnover and surface rugosity, and hydraulic activities and porewater bioadvection. Integrative metrics of ecosystem function in some cases differentiate among the systems (gross primary production) and in others do not (photosynthetic efficiency). Analyses based on behaviors and activities revealed important ecosystem functional differences and can dramatically improve our ability to model the impact of stressors on ecosystem and global processes. PMID:27230562

Same pattern, different mechanism: Locking onto the role of key species in seafloor ecosystem process.

PubMed

Woodin, Sarah Ann; Volkenborn, Nils; Pilditch, Conrad A; Lohrer, Andrew M; Wethey, David S; Hewitt, Judi E; Thrush, Simon F

2016-05-27

Seafloor biodiversity is a key mediator of ecosystem functioning, but its role is often excluded from global budgets or simplified to black boxes in models. New techniques allow quantification of the behavior of animals living below the sediment surface and assessment of the ecosystem consequences of complex interactions, yielding a better understanding of the role of seafloor animals in affecting key processes like primary productivity. Combining predictions based on natural history, behavior of key benthic species and environmental context allow assessment of differences in functioning and process, even when the measured ecosystem property in different systems is similar. Data from three sedimentary systems in New Zealand illustrate this. Analysis of the behaviors of the infaunal ecosystem engineers in each system revealed three very different mechanisms driving ecosystem function: density and excretion, sediment turnover and surface rugosity, and hydraulic activities and porewater bioadvection. Integrative metrics of ecosystem function in some cases differentiate among the systems (gross primary production) and in others do not (photosynthetic efficiency). Analyses based on behaviors and activities revealed important ecosystem functional differences and can dramatically improve our ability to model the impact of stressors on ecosystem and global processes.

Re-orienting discussions of scientific explanation: A functional perspective.

PubMed

Woody, Andrea I

2015-08-01

Philosophy of science offers a rich lineage of analysis concerning the nature of scientific explanation, but the vast majority of this work, aiming to provide an analysis of the relation that binds a given explanans to its corresponding explanandum, presumes the proper analytic focus rests at the level of individual explanations. There are, however, other questions we could ask about explanation in science, such as: What role(s) does explanatory practice play in science? Shifting focus away from explanations, as achievements, toward explaining, as a coordinated activity of communities, the functional perspective aims to reveal how the practice of explanatory discourse functions within scientific communities given their more comprehensive aims and practices. In this paper, I outline the functional perspective, argue that taking the functional perspective can reveal important methodological roles for explanation in science, and consequently, that beginning here provides resources for developing more adequate responses to traditional concerns. In particular, through an examination of the ideal gas law, I emphasize the normative status of explanations within scientific communities and discuss how such status underwrites a compelling rationale for explanatory power as a theoretical virtue. Copyright © 2015 Elsevier Ltd. All rights reserved.

Saturation scanning of ubiquitin variants reveals a common hot spot for binding to USP2 and USP21.

PubMed

Leung, Isabel; Dekel, Ayelet; Shifman, Julia M; Sidhu, Sachdev S

2016-08-02

A detailed understanding of the molecular mechanisms whereby ubiquitin (Ub) recognizes enzymes in the Ub proteasome system is crucial for understanding the biological function of Ub. Many structures of Ub complexes have been solved and, in most cases, reveal a large structural epitope on a common face of the Ub molecule. However, owing to the generally weak nature of these interactions, it has been difficult to map in detail the functional contributions of individual Ub side chains to affinity and specificity. Here we took advantage of Ub variants (Ubvs) that bind tightly to particular Ub-specific proteases (USPs) and used phage display and saturation scanning mutagenesis to comprehensively map functional epitopes within the structural epitopes. We found that Ubvs that bind to USP2 or USP21 contain a remarkably similar core functional epitope, or "hot spot," consisting mainly of positions that are conserved as the wild type sequence, but also some positions that prefer mutant sequences. The Ubv core functional epitope contacts residues that are conserved in the human USP family, and thus it is likely important for the interactions of Ub across many family members.

The bacterial flagellar switch complex is getting more complex

PubMed Central

Cohen-Ben-Lulu, Galit N; Francis, Noreen R; Shimoni, Eyal; Noy, Dror; Davidov, Yaacov; Prasad, Krishna; Sagi, Yael; Cecchini, Gary; Johnstone, Rose M; Eisenbach, Michael

2008-01-01

The mechanism of function of the bacterial flagellar switch, which determines the direction of flagellar rotation and is essential for chemotaxis, has remained an enigma for many years. Here we show that the switch complex associates with the membrane-bound respiratory protein fumarate reductase (FRD). We provide evidence that FRD binds to preparations of isolated switch complexes, forms a 1:1 complex with the switch protein FliG, and that this interaction is required for both flagellar assembly and switching the direction of flagellar rotation. We further show that fumarate, known to be a clockwise/switch factor, affects the direction of flagellar rotation through FRD. These results not only uncover a new component important for switching and flagellar assembly, but they also reveal that FRD, an enzyme known to be primarily expressed and functional under anaerobic conditions in Escherichia coli, nonetheless, has important, unexpected functions under aerobic conditions. PMID:18337747

Non-metabolic functions of glycolytic enzymes in tumorigenesis.

PubMed

Yu, X; Li, S

2017-05-11

Cancer cells reprogram their metabolism to meet the requirement for survival and rapid growth. One hallmark of cancer metabolism is elevated aerobic glycolysis and reduced oxidative phosphorylation. Emerging evidence showed that most glycolytic enzymes are deregulated in cancer cells and play important roles in tumorigenesis. Recent studies revealed that all essential glycolytic enzymes can be translocated into nucleus where they participate in tumor progression independent of their canonical metabolic roles. These noncanonical functions include anti-apoptosis, regulation of epigenetic modifications, modulation of transcription factors and co-factors, extracellular cytokine, protein kinase activity and mTORC1 signaling pathway, suggesting that these multifaceted glycolytic enzymes not only function in canonical metabolism but also directly link metabolism to epigenetic and transcription programs implicated in tumorigenesis. These findings underscore our understanding about how tumor cells adapt to nutrient and fuel availability in the environment and most importantly, provide insights into development of cancer therapy.

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior.

PubMed

Hutchison, M A; Gu, X; Adrover, M F; Lee, M R; Hnasko, T S; Alvarez, V A; Lu, W

2018-05-01

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.

Species Pool Functional Diversity Plays a Hidden Role in Generating β-Diversity.

PubMed

Patrick, Christopher J; Brown, Bryan L

2018-05-01

Functional trait diversity is used as a way to infer mechanistic processes that drive community assembly. While functional diversity within communities is often viewed as a response variable, here we present and test a framework for how functional diversity among taxa in the regional species pool drives the assembly of communities among habitats. We predicted that species pool functional diversity should work with environmental heterogeneity to drive β-diversity. We tested these predictions by modeling empirical patterns in invertebrate communities from 570 streams in 52 watersheds. Our analysis of the field data provided strong support for the inclusion of both functional diversity and environmental heterogeneity in the models, and our predictions were supported when the community was analyzed all together. However, analyses within individual functional feeding guilds revealed strong context dependency in the relative importance of functional diversity, γ-richness, and environmental heterogeneity to β-diversity. We interpret the results to mean that functional diversity can play an important role in driving β-diversity; however, within guilds the nature of interspecific interactions and species pool size complicate the relationship. Future research should test this conceptual model across different ecosystems and in experimental settings using metacommunity mesocosms to enhance our understanding of the role that functional variation plays in generating spatial biodiversity patterns.

Combined Secretomics and Transcriptomics Revealed Cancer-Derived GDF15 is Involved in Diffuse-Type Gastric Cancer Progression and Fibroblast Activation.

PubMed

Ishige, Takayuki; Nishimura, Motoi; Satoh, Mamoru; Fujimoto, Mai; Fukuyo, Masaki; Semba, Toshihisa; Kado, Sayaka; Tsuchida, Sachio; Sawai, Setsu; Matsushita, Kazuyuki; Togawa, Akira; Matsubara, Hisahiro; Kaneda, Atsushi; Nomura, Fumio

2016-02-19

Gastric cancer is classified into two subtypes, diffuse and intestinal. The diffuse-type gastric cancer (DGC) has poorer prognosis, and the molecular pathology is not yet fully understood. The purpose of this study was to identify functional secreted molecules involved in DGC progression. We integrated the secretomics of six gastric cancer cell lines and gene expression analysis of gastric cancer tissues with publicly available microarray data. Hierarchical clustering revealed characteristic gene expression differences between diffuse- and intestinal-types. GDF15 was selected as a functional secreted molecule owing to high expression only in fetal tissues. Protein expression of GDF15 was higher in DGC cell lines and tissues. Serum levels of GDF15 were significant higher in DGC patients as compared with healthy individuals and chronic gastritis patients, and positively correlated with wall invasion and lymph node metastasis. In addition, the stimulation of GDF15 on NIH3T3 fibroblast enhanced proliferation and up-regulated expression of extracellular matrix genes, which were similar to TGF-β stimulation. These results indicate that GDF15 contributes to fibroblast activation. In conclusion, this study revealed that GDF15 may be a novel functional secreted molecule for DGC progression, possibly having important roles for cancer progression via the affecting fibroblast function, as well as TGF-β.

New insights into globoids of protein storage vacuoles in wheat aleurone using synchrotron soft X-ray microscopy

PubMed Central

Regvar, Marjana; Eichert, Diane; Kaulich, Burkhard; Gianoncelli, Alessandra; Pongrac, Paula; Vogel-Mikuš, Katarina; Kreft, Ivan

2011-01-01

Mature developed seeds are physiologically and biochemically committed to store nutrients, principally as starch, protein, oils, and minerals. The composition and distribution of elements inside the aleurone cell layer reflect their biogenesis, structural characteristics, and physiological functions. It is therefore of primary importance to understand the mechanisms underlying metal ion accumulation, distribution, storage, and bioavailability in aleurone subcellular organelles for seed fortification purposes. Synchrotron radiation soft X-ray full-field imaging mode (FFIM) and low-energy X-ray fluorescence (LEXRF) spectromicroscopy were applied to characterize major structural features and the subcellular distribution of physiologically important elements (Zn, Fe, Na, Mg, Al, Si, and P). These direct imaging methods reveal the accumulation patterns between the apoplast and symplast, and highlight the importance of globoids with phytic acid mineral salts and walls as preferential storage structures. C, N, and O chemical topographies are directly linked to the structural backbone of plant substructures. Zn, Fe, Na, Mg, Al, and P were linked to globoid structures within protein storage vacuoles with variable levels of co-localization. Si distribution was atypical, being contained in the aleurone apoplast and symplast, supporting a physiological role for Si in addition to its structural function. These results reveal that the immobilization of metals within the observed endomembrane structures presents a structural and functional barrier and affects bioavailability. The combination of high spatial and chemical X-ray microscopy techniques highlights how in situ analysis can yield new insights into the complexity of the wheat aleurone layer, whose precise biochemical composition, morphology, and structural characteristics are still not unequivocally resolved. PMID:21447756

Characterisation of Four LIM Protein-Encoding Genes Involved in Infection-Related Development and Pathogenicity by the Rice Blast Fungus Magnaporthe oryzae

PubMed Central

Li, Ya; Yue, Xiaofeng; Que, Yawei; Yan, Xia; Ma, Zhonghua; Talbot, Nicholas J.; Wang, Zhengyi

2014-01-01

LIM domain proteins contain contiguous double-zinc finger domains and play important roles in cytoskeletal re-organisation and organ development in multi-cellular eukaryotes. Here, we report the characterization of four genes encoding LIM proteins in the rice blast fungus Magnaporthe oryzae. Targeted gene replacement of either the paxillin-encoding gene, PAX1, or LRG1 resulted in a significant reduction in hyphal growth and loss of pathogenicity, while deletion of RGA1 caused defects in conidiogenesis and appressorium development. A fourth LIM domain gene, LDP1, was not required for infection-associated development by M. oryzae. Live cell imaging revealed that Lrg1-GFP and Rga1-GFP both localize to septal pores, while Pax1-GFP is present in the cytoplasm. To explore the function of individual LIM domains, we carried out systematic deletion of each LIM domain, which revealed the importance of the Lrg1-LIM2 and Lrg1-RhoGAP domains for Lrg1 function and overlapping functions of the three LIM domains of Pax1. Interestingly, deletion of either PAX1 or LRG1 led to decreased sensitivity to cell wall-perturbing agents, such as Congo Red and SDS (sodium dodecyl sulfate). qRT-PCR analysis demonstrated the importance of both Lrg1 and Pax1 to regulation of genes associated with cell wall biogenesis. When considered together, our results indicate that LIM domain proteins are key regulators of infection-associated morphogenesis by the rice blast fungus. PMID:24505448

How cancer cells dictate their microenvironment: present roles of extracellular vesicles.

PubMed

Naito, Yutaka; Yoshioka, Yusuke; Yamamoto, Yusuke; Ochiya, Takahiro

2017-02-01

Intercellular communication plays an important role in cancer initiation and progression through secretory molecules, including growth factors and cytokines. Recent advances have revealed that small membrane vesicles, termed extracellular vesicles (EVs), served as a regulatory agent in the intercellular communication of cancer. EVs enable the transfer of functional molecules, including proteins, mRNA and microRNAs (miRNAs), into recipient cells. Cancer cells utilize EVs to dictate the unique phenotype of surrounding cells, thereby promoting cancer progression. Against such "education" by cancer cells, non-tumoral cells suppress cancer initiation and progression via EVs. Therefore, researchers consider EVs to be important cues to clarify the molecular mechanisms of cancer biology. Understanding the functions of EVs in cancer progression is an important aspect of cancer biology that has not been previously elucidated. In this review, we summarize experimental data that indicate the pivotal roles of EVs in cancer progression.

Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics

PubMed Central

Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M.; Abel, Steven M.; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S.; Hansen, Scott D.; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K.; Kuriyan, John; Groves, Jay T.

2014-01-01

Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras–guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. PMID:24994643

The soil microbiome — from metagenomics to metaphenomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jansson, Janet K.; Hofmockel, Kirsten S.

Soil microorganisms carry out important processes, including support of plant growth and cycling of carbon and other nutrients. However, the majority of soil microbes have not yet been isolated and their functions are largely unknown. Although metagenomic sequencing reveals microbial identities and functional gene information, it includes DNA from microbes with vastly varying physiological states. Therefore, metagenomics is only predictive of community functional potential. We posit that the next frontier lies in understanding the metaphenome, the product of the combined genetic potential of the microbiome and available resources. Here in this paper we describe examples of opportunities towards gaining understandingmore » of the soil metaphenome.« less

The soil microbiome — from metagenomics to metaphenomics

DOE PAGES

Jansson, Janet K.; Hofmockel, Kirsten S.

2018-02-15

Soil microorganisms carry out important processes, including support of plant growth and cycling of carbon and other nutrients. However, the majority of soil microbes have not yet been isolated and their functions are largely unknown. Although metagenomic sequencing reveals microbial identities and functional gene information, it includes DNA from microbes with vastly varying physiological states. Therefore, metagenomics is only predictive of community functional potential. We posit that the next frontier lies in understanding the metaphenome, the product of the combined genetic potential of the microbiome and available resources. Here in this paper we describe examples of opportunities towards gaining understandingmore » of the soil metaphenome.« less

Importance of van der Waals interaction on structural, vibrational, and thermodynamic properties of NaCl

NASA Astrophysics Data System (ADS)

Marcondes, Michel L.; Wentzcovitch, Renata M.; Assali, Lucy V. C.

2018-05-01

Thermal equations of state (EOS) are essential in several scientific domains. However, experimental determination of EOS parameters may be limited at extreme conditions, therefore, ab initio calculations have become an important method to obtain them. Density functional theory (DFT) and its extensions with various degrees of approximations for the exchange and correlation (XC) energy is the method of choice, but large errors in the EOS parameters are still common. The alkali halides have been problematic from the onset of this field and the quest for appropriate DFT functionals for such ionic and relatively weakly bonded systems has remained an active topic of research. Here we use DFT + van der Waals functionals to calculate vibrational properties, thermal EOS, thermodynamic properties, and the B1 to B2 phase boundary of NaCl with high precision. Our results reveal a remarkable improvement over the performance of standard local density approximation and generalized gradient approximation functionals for all these properties and phase transition boundary, as well as great sensitivity of anharmonic effects on the choice of XC functional.

Nitrotoga-like bacteria are previously unrecognized key nitrite oxidizers in full-scale wastewater treatment plants.

PubMed

Lücker, Sebastian; Schwarz, Jasmin; Gruber-Dorninger, Christiane; Spieck, Eva; Wagner, Michael; Daims, Holger

2015-03-01

Numerous past studies have shown members of the genus Nitrospira to be the predominant nitrite-oxidizing bacteria (NOB) in nitrifying wastewater treatment plants (WWTPs). Only recently, the novel NOB 'Candidatus Nitrotoga arctica' was identified in permafrost soil and a close relative was enriched from activated sludge. Still, little is known about diversity, distribution and functional importance of Nitrotoga in natural and engineered ecosystems. Here we developed Nitrotoga 16S rRNA-specific PCR primers and fluorescence in situ hybridization (FISH) probes, which were applied to screen activated sludge samples from 20 full-scale WWTPs. Nitrotoga-like bacteria were detected by PCR in 11 samples and reached abundances detectable by FISH in seven sludges. They coexisted with Nitrospira in most of these WWTPs, but constituted the only detectable NOB in two systems. Quantitative FISH revealed that Nitrotoga accounted for nearly 2% of the total bacterial community in one of these plants, a number comparable to Nitrospira abundances in other WWTPs. Spatial statistics revealed that Nitrotoga coaggregated with ammonia-oxidizing bacteria, strongly supporting a functional role in nitrite oxidation. This activity was confirmed by FISH in combination with microradiography, which revealed nitrite-dependent autotrophic carbon fixation by Nitrotoga in situ. Correlation of the presence or absence with WWTP operational parameters indicated low temperatures as a main factor supporting high Nitrotoga abundances, although in incubation experiments these NOB remained active over an unexpected range of temperatures, and also at different ambient nitrite concentrations. In conclusion, this study demonstrates that Nitrotoga can be functionally important nitrite oxidizers in WWTPs and can even represent the only known NOB in engineered systems.

Reversible Unfolding of Rhomboid Intramembrane Proteases.

PubMed

Panigrahi, Rashmi; Arutyunova, Elena; Panwar, Pankaj; Gimpl, Katharina; Keller, Sandro; Lemieux, M Joanne

2016-03-29

Denaturant-induced unfolding of helical membrane proteins provides insights into their mechanism of folding and domain organization, which take place in the chemically heterogeneous, anisotropic environment of a lipid membrane. Rhomboid proteases are intramembrane proteases that play key roles in various diseases. Crystal structures have revealed a compact helical bundle with a buried active site, which requires conformational changes for the cleavage of transmembrane substrates. A dimeric form of the rhomboid protease has been shown to be important for activity. In this study, we examine the mechanism of refolding for two distinct rhomboids to gain insight into their secondary structure-activity relationships. Although helicity is largely abolished in the unfolded states of both proteins, unfolding is completely reversible for HiGlpG but only partially reversible for PsAarA. Refolding of both proteins results in reassociation of the dimer, with a 90% regain of catalytic activity for HiGlpG but only a 70% regain for PsAarA. For both proteins, a broad, gradual transition from the native, folded state to the denatured, partly unfolded state was revealed with the aid of circular dichroism spectroscopy as a function of denaturant concentration, thus arguing against a classical two-state model as found for many globular soluble proteins. Thermal denaturation has irreversible destabilizing effects on both proteins, yet reveals important functional details regarding substrate accessibility to the buried active site. This concerted biophysical and functional analysis demonstrates that HiGlpG, with a simple six-transmembrane-segment organization, is more robust than PsAarA, which has seven predicted transmembrane segments, thus rendering HiGlpG amenable to in vitro studies of membrane-protein folding. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

DISC1 Causes Associative Memory and Neurodevelopmental Defects in Fruit Flies

PubMed Central

Furukubo-Tokunaga, Katsuo; Kurita, Kazuki; Honjo, Ken; Pandey, Himani; Ando, Tetsuya; Takayama, Kojiro; Arai, Yuko; Mochizuki, Hiroaki; Ando, Mai; Kamiya, Atsushi; Sawa, Akira

2016-01-01

Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino terminal domain (46–290) for memory suppression whereas carboxyl domain (598–854) and the amino terminal residues (1–45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion constructs reveal that protein domains 598–854 and 349–402 are both required for the suppression of axonal branching while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403–596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403–596 and 349–402 for synaptic suppression, while amino terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses. PMID:26976042

An exemplar-based approach to individualized parcellation reveals the need for sex specific functional networks.

PubMed

Salehi, Mehraveh; Karbasi, Amin; Shen, Xilin; Scheinost, Dustin; Constable, R Todd

2018-04-15

Recent work with functional connectivity data has led to significant progress in understanding the functional organization of the brain. While the majority of the literature has focused on group-level parcellation approaches, there is ample evidence that the brain varies in both structure and function across individuals. In this work, we introduce a parcellation technique that incorporates delineation of functional networks both at the individual- and group-level. The proposed technique deploys the notion of "submodularity" to jointly parcellate the cerebral cortex while establishing an inclusive correspondence between the individualized functional networks. Using this parcellation technique, we successfully established a cross-validated predictive model that predicts individuals' sex, solely based on the parcellation schemes (i.e. the node-to-network assignment vectors). The sex prediction finding illustrates that individualized parcellation of functional networks can reveal subgroups in a population and suggests that the use of a global network parcellation may overlook fundamental differences in network organization. This is a particularly important point to consider in studies comparing patients versus controls or even patient subgroups. Network organization may differ between individuals and global configurations should not be assumed. This approach to the individualized study of functional organization in the brain has many implications for both neuroscience and clinical applications. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical functionalization of graphene to augment stem cell osteogenesis and inhibit biofilm formation on polymer composites for orthopedic applications.

PubMed

Kumar, Sachin; Raj, Shammy; Kolanthai, Elayaraja; Sood, A K; Sampath, S; Chatterjee, Kaushik

2015-02-11

Toward designing the next generation of resorbable biomaterials for orthopedic applications, we studied poly(ε-caprolactone) (PCL) composites containing graphene. The role, if any, of the functionalization of graphene on mechanical properties, stem cell response, and biofilm formation was systematically evaluated. PCL composites of graphene oxide (GO), reduced GO (RGO), and amine-functionalized GO (AGO) were prepared at different filler contents (1%, 3%, and 5%). Although the addition of the nanoparticles to PCL markedly increased the storage modulus, this increase was largest for GO followed by AGO and RGO. In vitro cell studies revealed that the AGO and GO particles significantly increased human mesenchymal stem cell proliferation. AGO was most effective in augmenting stem cell osteogenesis leading to mineralization. Bacterial studies revealed that interaction with functionalized GO induced bacterial cell death because of membrane damage, which was further accentuated by amine groups in AGO. As a result, AGO composites were best at inhibiting biofilm formation. The synergistic effect of oxygen containing functional groups and amine groups on AGO imparts the optimal combination of improved modulus, favorable stem cell response, and biofilm inhibition in AGO-reinforced composites desired for orthopedic applications. This work elucidates the importance of chemical functionalization of graphene in polymer composites for biomedical applications.

Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology.

PubMed

Gibson, Molly K; Forsberg, Kevin J; Dantas, Gautam

2015-01-01

Antibiotic resistance is a dire clinical problem with important ecological dimensions. While antibiotic resistance in human pathogens continues to rise at alarming rates, the impact of environmental resistance on human health is still unclear. To investigate the relationship between human-associated and environmental resistomes, we analyzed functional metagenomic selections for resistance against 18 clinically relevant antibiotics from soil and human gut microbiota as well as a set of multidrug-resistant cultured soil isolates. These analyses were enabled by Resfams, a new curated database of protein families and associated highly precise and accurate profile hidden Markov models, confirmed for antibiotic resistance function and organized by ontology. We demonstrate that the antibiotic resistance functions that give rise to the resistance profiles observed in environmental and human-associated microbial communities significantly differ between ecologies. Antibiotic resistance functions that most discriminate between ecologies provide resistance to β-lactams and tetracyclines, two of the most widely used classes of antibiotics in the clinic and agriculture. We also analyzed the antibiotic resistance gene composition of over 6000 sequenced microbial genomes, revealing significant enrichment of resistance functions by both ecology and phylogeny. Together, our results indicate that environmental and human-associated microbial communities harbor distinct resistance genes, suggesting that antibiotic resistance functions are largely constrained by ecology.

Tea plant SWEET transporters: expression profiling, sugar transport, and the involvement of CsSWEET16 in modifying cold tolerance in Arabidopsis.

PubMed

Wang, Lu; Yao, Lina; Hao, Xinyuan; Li, Nana; Qian, Wenjun; Yue, Chuan; Ding, Changqing; Zeng, Jianming; Yang, Yajun; Wang, Xinchao

2018-04-01

Thirteen SWEET transporters were identified in Camellia sinensis and the cold-suppression gene CsSWEET16 contributed to sugar compartmentation across the vacuole and function in modifying cold tolerance in Arabidopsis. The sugars will eventually be exported transporters (SWEET) family of sugar transporters in plants is a recently identified protein family of sugar uniporters that contain seven transmembrane helices harbouring two MtN3 motifs. SWEETs play important roles in various biological processes, including plant responses to environmental stimuli. In this study, 13 SWEET transporters were identified in Camellia sinensis and were divided into four clades. Transcript abundances of CsSWEET genes were detected in various tissues. CsSWEET1a/1b/2a/2b/2c/3/9b/16/17 were expressed in all of the selected tissues, whereas the expression of CsSWEET5/7/9a/15 was not detected in some tissues, including those of mature leaves. Expression analysis of nine CsSWEET genes in leaves in response to abiotic stresses, natural cold acclimation and Colletotrichum camelliae infection revealed that eight CsSWEET genes responded to abiotic stress, while CsSWEET3 responded to C. camelliae infection. Functional analysis of 13 CsSWEET activities in yeast revealed that CsSWEET1a/1b/7/17 exhibit transport activity for glucose analogues and other types of hexose molecules. Further characterization of the cold-suppression gene CsSWEET16 revealed that this gene is localized in the vacuolar membrane. CsSWEET16 contributed to sugar compartmentation across the vacuole and function in modifying cold tolerance in Arabidopsis. Together, these findings demonstrate that CsSWEET genes play important roles in the response to abiotic and biotic stresses in tea plants and provide insights into the characteristics of SWEET genes in tea plants, which could serve as the basis for further functional identification of such genes.

Trends in Taxonomic and Functional Composition of Soil Microbiome Along a Precipitation Gradient in Israel.

PubMed

Tripathi, Binu M; Moroenyane, Itumeleng; Sherman, Chen; Lee, Yoo Kyung; Adams, Jonathan M; Steinberger, Yosef

2017-07-01

The soil microbiome is important for the functioning of terrestrial ecosystems. However, the impacts of climate on taxonomic and functional diversity of soil microbiome are not well understood. A precipitation gradient along regional scale transects may offer a model setting for understanding the effect of climate on the composition and function of the soil microbiome. Here, we compared taxonomic and functional attributes of soil microorganisms in arid, semiarid, Mediterranean, and humid Mediterranean climatic conditions of Israel using shotgun metagenomic sequencing. We hypothesized that there would be a distinct taxonomic and functional soil community for each precipitation zone, with arid environments having lower taxonomic and functional diversity, greater relative abundance of stress response and sporulation-related genes, and lower relative abundance of genes related to nutrient cycling and degradation of complex organic compounds. As hypothesized, our results showed a distinct taxonomic and functional community in each precipitation zone, revealing differences in soil taxonomic and functional selection in the different climates. Although the taxonomic diversity remained similar across all sites, the functional diversity was-as hypothesized-lower in the arid environments, suggesting that functionality is more constrained in "extreme" environments. Also, with increasing aridity, we found a significant increase in genes related to dormancy/sporulation and a decrease in those related to nutrient cycling (genes related to nitrogen, potassium, and sulfur metabolism), respectively. However, relative abundance of genes related to stress response were lower in arid soils. Overall, these results indicate that climatic conditions play an important role in shaping taxonomic and functional attributes of soil microbiome. These findings have important implications for understanding the impacts of climate change (e.g., precipitation change) on structure and function of the soil microbiome.

Genome-wide transcriptional analysis of flagellar regeneration in Chlamydomonas reinhardtii identifies orthologs of ciliary disease genes

NASA Technical Reports Server (NTRS)

Stolc, Viktor; Samanta, Manoj Pratim; Tongprasit, Waraporn; Marshall, Wallace F.

2005-01-01

The important role that cilia and flagella play in human disease creates an urgent need to identify genes involved in ciliary assembly and function. The strong and specific induction of flagellar-coding genes during flagellar regeneration in Chlamydomonas reinhardtii suggests that transcriptional profiling of such cells would reveal new flagella-related genes. We have conducted a genome-wide analysis of RNA transcript levels during flagellar regeneration in Chlamydomonas by using maskless photolithography method-produced DNA oligonucleotide microarrays with unique probe sequences for all exons of the 19,803 predicted genes. This analysis represents previously uncharacterized whole-genome transcriptional activity profiling study in this important model organism. Analysis of strongly induced genes reveals a large set of known flagellar components and also identifies a number of important disease-related proteins as being involved with cilia and flagella, including the zebrafish polycystic kidney genes Qilin, Reptin, and Pontin, as well as the testis-expressed tubby-like protein TULP2.

Functional diversification of sea urchin ABCC1 (MRP1) by alternative splicing.

PubMed

Gökirmak, Tufan; Campanale, Joseph P; Reitzel, Adam M; Shipp, Lauren E; Moy, Gary W; Hamdoun, Amro

2016-06-01

The multidrug resistance protein (MRP) family encodes a diverse repertoire of ATP-binding cassette (ABC) transporters with multiple roles in development, disease, and homeostasis. Understanding MRP evolution is central to unraveling their roles in these diverse processes. Sea urchins occupy an important phylogenetic position for understanding the evolution of vertebrate proteins and have been an important invertebrate model system for study of ABC transporters. We used phylogenetic analyses to examine the evolution of MRP transporters and functional approaches to identify functional forms of sea urchin MRP1 (also known as SpABCC1). SpABCC1, the only MRP homolog in sea urchins, is co-orthologous to human MRP1, MRP3, and MRP6 (ABCC1, ABCC3, and ABCC6) transporters. However, efflux assays revealed that alternative splicing of exon 22, a region critical for substrate interactions, could diversify functions of sea urchin MRP1. Phylogenetic comparisons also indicate that while MRP1, MRP3, and MRP6 transporters potentially arose from a single transporter in basal deuterostomes, alternative splicing appears to have been the major mode of functional diversification in invertebrates, while duplication may have served a more important role in vertebrates. These results provide a deeper understanding of the evolutionary origins of MRP transporters and the potential mechanisms used to diversify their functions in different groups of animals. Copyright © 2016 the American Physiological Society.

Functional diversification of sea urchin ABCC1 (MRP1) by alternative splicing

PubMed Central

Gökirmak, Tufan; Campanale, Joseph P.; Reitzel, Adam M.; Shipp, Lauren E.; Moy, Gary W.

2016-01-01

The multidrug resistance protein (MRP) family encodes a diverse repertoire of ATP-binding cassette (ABC) transporters with multiple roles in development, disease, and homeostasis. Understanding MRP evolution is central to unraveling their roles in these diverse processes. Sea urchins occupy an important phylogenetic position for understanding the evolution of vertebrate proteins and have been an important invertebrate model system for study of ABC transporters. We used phylogenetic analyses to examine the evolution of MRP transporters and functional approaches to identify functional forms of sea urchin MRP1 (also known as SpABCC1). SpABCC1, the only MRP homolog in sea urchins, is co-orthologous to human MRP1, MRP3, and MRP6 (ABCC1, ABCC3, and ABCC6) transporters. However, efflux assays revealed that alternative splicing of exon 22, a region critical for substrate interactions, could diversify functions of sea urchin MRP1. Phylogenetic comparisons also indicate that while MRP1, MRP3, and MRP6 transporters potentially arose from a single transporter in basal deuterostomes, alternative splicing appears to have been the major mode of functional diversification in invertebrates, while duplication may have served a more important role in vertebrates. These results provide a deeper understanding of the evolutionary origins of MRP transporters and the potential mechanisms used to diversify their functions in different groups of animals. PMID:27053522

Oral Rehabilitation of a Patient with Amelogenesis Imperfecta

PubMed Central

Cogulu, Dilsah; Becerik, Sema; Emingil, Gülnur; Hart, P. Suzanne; Hart, Thomas C.

2014-01-01

Amelogenesis imperfecta is a hereditary disorder that causes defective enamel development in the primary and permanent teeth. Clinical treatment is important to address the esthetic appearance of affected teeth, reduce dentinal sensitivity, preserve tooth structure, and optimize masticatory function. The purpose of this case report was to describe the diagnosis, treatment planning, and dental rehabilitation of a patient with autosomal recessive amelogenesis imperfecta. The patient was followed for 5 years, and evaluation 3 years after restorations revealed no pathology associated with the rehabilitation. The patient’s esthetic and functional expectations were satisfied. PMID:20108745

Building Blocks of the Nexin-Dynein Regulatory Complex in Chlamydomonas Flagella*

PubMed Central

Lin, Jianfeng; Tritschler, Douglas; Song, Kangkang; Barber, Cynthia F.; Cobb, Jennifer S.; Porter, Mary E.; Nicastro, Daniela

2011-01-01

The directional flow generated by motile cilia and flagella is critical for many processes, including human development and organ function. Normal beating requires the control and coordination of thousands of dynein motors, and the nexin-dynein regulatory complex (N-DRC) has been identified as an important regulatory node for orchestrating dynein activity. The nexin link appears to be critical for the transformation of dynein-driven, linear microtubule sliding to flagellar bending, yet the molecular composition and mechanism of the N-DRC remain largely unknown. Here, we used proteomics with special attention to protein phosphorylation to analyze the composition of the N-DRC and to determine which subunits may be important for signal transduction. Two-dimensional electrophoresis and MALDI-TOF mass spectrometry of WT and mutant flagellar axonemes from Chlamydomonas identified 12 N-DRC-associated proteins, including all seven previously observed N-DRC components. Sequence and PCR analyses identified the mutation responsible for the phenotype of the sup-pf-4 strain, and biochemical comparison with a radial spoke mutant revealed two components that may link the N-DRC and the radial spokes. Phosphoproteomics revealed eight proteins with phosphorylated isoforms for which the isoform patterns changed with the genotype as well as two components that may play pivotal roles in N-DRC function through their phosphorylation status. These data were assembled into a model of the N-DRC that explains aspects of its regulatory function. PMID:21700706

RNA-seq analyses reveal insights into the function of respiratory nitrate reductase of the diazotroph Herbaspirillum seropedicae.

PubMed

Bonato, Paloma; Batista, Marcelo B; Camilios-Neto, Doumit; Pankievicz, Vânia C S; Tadra-Sfeir, Michelle Z; Monteiro, Rose Adele; Pedrosa, Fabio O; Souza, Emanuel M; Chubatsu, Leda S; Wassem, Roseli; Rigo, Liu Un

2016-09-01

Herbaspirillum seropedicae is a nitrogen-fixing β-proteobacterium that associates with roots of gramineous plants. In silico analyses revealed that H. seropedicae genome has genes encoding a putative respiratory (NAR) and an assimilatory nitrate reductase (NAS). To date, little is known about nitrate metabolism in H. seropedicae, and, as this bacterium cannot respire nitrate, the function of NAR remains unknown. This study aimed to investigate the function of NAR in H. seropedicae and how it metabolizes nitrate in a low aerated-condition. RNA-seq transcriptional profiling in the presence of nitrate allowed us to pinpoint genes important for nitrate metabolism in H. seropedicae, including nitrate transporters and regulatory proteins. Additionally, both RNA-seq data and physiological characterization of a mutant in the catalytic subunit of NAR (narG mutant) showed that NAR is not required for nitrate assimilation but is required for: (i) production of high levels of nitrite, (ii) production of NO and (iii) dissipation of redox power, which in turn lead to an increase in carbon consumption. In addition, wheat plants showed an increase in shoot dry weight only when inoculated with H. seropedicae wild type, but not with the narG mutant, suggesting that NAR is important to H. seropedicae-wheat interaction. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease.

PubMed

Torres, Matthew P; Dewhurst, Henry; Sundararaman, Niveda

2016-11-01

Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable body of potential regulatory elements that impact hundreds of different biological processes important in eukaryotic biology and human health. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease*

PubMed Central

Dewhurst, Henry; Sundararaman, Niveda

2016-01-01

Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable body of potential regulatory elements that impact hundreds of different biological processes important in eukaryotic biology and human health. PMID:27697855

Executive functioning predicts reading, mathematics, and theory of mind during the elementary years.

PubMed

Cantin, Rachelle H; Gnaedinger, Emily K; Gallaway, Kristin C; Hesson-McInnis, Matthew S; Hund, Alycia M

2016-06-01

The goal of this study was to specify how executive functioning components predict reading, mathematics, and theory of mind performance during the elementary years. A sample of 93 7- to 10-year-old children completed measures of working memory, inhibition, flexibility, reading, mathematics, and theory of mind. Path analysis revealed that all three executive functioning components (working memory, inhibition, and flexibility) mediated age differences in reading comprehension, whereas age predicted mathematics and theory of mind directly. In addition, reading mediated the influence of executive functioning components on mathematics and theory of mind, except that flexibility also predicted mathematics directly. These findings provide important details about the development of executive functioning, reading, mathematics, and theory of mind during the elementary years. Copyright © 2016 Elsevier Inc. All rights reserved.

Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair

PubMed Central

Redpath, G. M. I.; Woolger, N.; Piper, A. K.; Lemckert, F. A.; Lek, A.; Greer, P. A.; North, K. N.; Cooper, S. T.

2014-01-01

Dysferlin and calpain are important mediators of the emergency response to repair plasma membrane injury. Our previous research revealed that membrane injury induces cleavage of dysferlin to release a synaptotagmin-like C-terminal module we termed mini-dysferlinC72. Here we show that injury-activated cleavage of dysferlin is mediated by the ubiquitous calpains via a cleavage motif encoded by alternately spliced exon 40a. An exon 40a–specific antibody recognizing cleaved mini-dysferlinC72 intensely labels the circumference of injury sites, supporting a key role for dysferlinExon40a isoforms in membrane repair and consistent with our evidence suggesting that the calpain-cleaved C-terminal module is the form specifically recruited to injury sites. Calpain cleavage of dysferlin is a ubiquitous response to membrane injury in multiple cell lineages and occurs independently of the membrane repair protein MG53. Our study links calpain and dysferlin in the calcium-activated vesicle fusion of membrane repair, placing calpains as upstream mediators of a membrane repair cascade that elicits cleaved dysferlin as an effector. Of importance, we reveal that myoferlin and otoferlin are also cleaved enzymatically to release similar C-terminal modules, bearing two C2 domains and a transmembrane domain. Evolutionary preservation of this feature highlights its functional importance and suggests that this highly conserved C-terminal region of ferlins represents a functionally specialized vesicle fusion module. PMID:25143396

Cassava root membrane proteome reveals activities during storage root maturation.

PubMed

Naconsie, Maliwan; Lertpanyasampatha, Manassawe; Viboonjun, Unchera; Netrphan, Supatcharee; Kuwano, Masayoshi; Ogasawara, Naotake; Narangajavana, Jarunya

2016-01-01

Cassava (Manihot esculenta Crantz) is one of the most important crops of Thailand. Its storage roots are used as food, feed, starch production, and be the important source for biofuel and biodegradable plastic production. Despite the importance of cassava storage roots, little is known about the mechanisms involved in their formation. This present study has focused on comparison of the expression profiles of cassava root proteome at various developmental stages using two-dimensional gel electrophoresis and LC-MS/MS. Based on an anatomical study using Toluidine Blue, the secondary growth was confirmed to be essential during the development of cassava storage root. To investigate biochemical processes occurring during storage root maturation, soluble and membrane proteins were isolated from storage roots harvested from 3-, 6-, 9-, and 12-month-old cassava plants. The proteins with differential expression pattern were analysed and identified to be associated with 8 functional groups: protein folding and degradation, energy, metabolism, secondary metabolism, stress response, transport facilitation, cytoskeleton, and unclassified function. The expression profiling of membrane proteins revealed the proteins involved in protein folding and degradation, energy, and cell structure were highly expressed during early stages of development. Integration of these data along with the information available in genome and transcriptome databases is critical to expand knowledge obtained solely from the field of proteomics. Possible role of identified proteins were discussed in relation with the activities during storage root maturation in cassava.

Functional genetic divergence in high CO2 adapted Emiliania huxleyi populations.

PubMed

Lohbeck, Kai T; Riebesell, Ulf; Collins, Sinéad; Reusch, Thorsten B H

2013-07-01

Predicting the impacts of environmental change on marine organisms, food webs, and biogeochemical cycles presently relies almost exclusively on short-term physiological studies, while the possibility of adaptive evolution is often ignored. Here, we assess adaptive evolution in the coccolithophore Emiliania huxleyi, a well-established model species in biological oceanography, in response to ocean acidification. We previously demonstrated that this globally important marine phytoplankton species adapts within 500 generations to elevated CO2 . After 750 and 1000 generations, no further fitness increase occurred, and we observed phenotypic convergence between replicate populations. We then exposed adapted populations to two novel environments to investigate whether or not the underlying basis for high CO2 -adaptation involves functional genetic divergence, assuming that different novel mutations become apparent via divergent pleiotropic effects. The novel environment "high light" did not reveal such genetic divergence whereas growth in a low-salinity environment revealed strong pleiotropic effects in high CO2 adapted populations, indicating divergent genetic bases for adaptation to high CO2 . This suggests that pleiotropy plays an important role in adaptation of natural E. huxleyi populations to ocean acidification. Our study highlights the potential mutual benefits for oceanography and evolutionary biology of using ecologically important marine phytoplankton for microbial evolution experiments. © 2012 The Author(s). Evolution © 2012 The Society for the Study of Evolution.

Functional composition of epifauna in the south-eastern North Sea in relation to habitat characteristics and fishing effort

NASA Astrophysics Data System (ADS)

Neumann, Hermann; Diekmann, Rabea; Kröncke, Ingrid

2016-02-01

Analysis of ecosystem functioning is essential to describe the ecological status of ecosystems and is therefore directly requested in international directives. There is a lack of knowledge regarding functional aspects of benthic communities and their environmental and anthropogenic driving forces in the southern North Sea. This study linked functional composition of epibenthic communities to environmental conditions and fishing effort and investigated spatial correlations between habitat characteristics to gain insight into potential synergistic and/or cumulative effects. Functional composition of epifauna was assessed by using biological trait analysis (BTA), which considered 15 ecological traits of 54 species. Functional composition was related to ten predictor variables derived from sediment composition, bottom temperature and salinity, hydrodynamics, annual primary production and fishing effort. Our results revealed significantly different functional composition between the Dogger Bank, the Oyster Ground, the West and North Frisian coast. Mobility, feeding type, size and adult longevity were the most important traits differentiating the communities. A high proportion of trait modalities related to an opportunistic life mode were obvious in coastal areas especially at the West Frisian coast and in the area of the Frisian Front indicating disturbed communities. In contrast, functional composition in the Dogger Bank area indicated undisturbed communities with prevalence of large, long-lived and permanently attached species being sensitive towards disturbance such as fishing. Tidal stress, mud content of sediments, salinity, stratification and fishing effort were found to be the most important habitat characteristics shaping functional composition. Strong correlations were found between variables, especially between those which changed gradually from the coast to offshore areas including fishing effort. Unfavourable extremes of these factors in coastal areas resulted in disturbed epibenthic communities, while the relative influence of a single factor on functional composition cannot be quantified. Coastal communities seemed to be well adapted to disturbance and the prevalence of opportunistic trait modalities not necessarily revealed a poor ecological status according to the Marine Strategy Framework Directive (MSFD). The integration of functional aspects into the assessment of ecosystem health is recommended, since widely used structural measures failed in naturally disturbed habitats.

Transcriptome profiling of petal abscission zone and functional analysis of AUX/IAA family genes reveal that RhIAA16 is involved in petal shedding in rose

USDA-ARS?s Scientific Manuscript database

Rose is one of the most important cut flowers among ornamental plants. Rose flower longevity is largely dependent on the timing of petal shedding occurrence. To understand the molecular mechanism underlying petal abscission in rose, we performed transcriptome profiling of the petal abscission zone d...

Fan-Shaped Body Neurons Are Involved in "Period"-Dependent Regulation of Long-Term Courtship Memory in "Drosophila"

ERIC Educational Resources Information Center

Sakai, Takaomi; Inami, Show; Sato, Shoma; Kitamoto, Toshihiro

2012-01-01

In addition to its established function in the regulation of circadian rhythms, the "Drosophila" gene "period" ("per") also plays an important role in processing long-term memory (LTM). Here, we used courtship conditioning as a learning paradigm and revealed that (1) overexpression and knocking down of "per" in subsets of brain neurons enhance and…

Genetic analysis of teat number in pigs reveals some developmental pathways independent of vertebra number and several loci which only affect a specific side

USDA-ARS?s Scientific Manuscript database

Background: Number of functional teats is an important trait in commercial swine production. As litter size increases, the number of teats must also increase to supply nutrition to all piglets. Therefore, a genome-wide association analysis was conducted to identify genomic regions that affect this ...

There Is More to the Dissection of a Pig's Heart

ERIC Educational Resources Information Center

Lee, Yeung Chung

2004-01-01

The dissection of the mammalian heart in secondary biology classes need not be restricted to revealing the internal structure of the heart and its function. It could also be used to demonstrate other important aspects of blood circulation, including the blood supply to the heart itself as well as the causes and effects of coronary heart disease.…

Plain Speaking: A Theory and Grammar of Spontaneous Discourse.

DTIC Science & Technology

1981-06-01

reveals surface linguistic phenomena that contradict traditional theories based on single sentence studies and longer texts artificially constructed...Excerpt 1 , Chapter 1, to illustrate the importance of functional development and discernment. In the midst of discussing the case of two twins under study ...his social interactive behavior in kindergarten. Authority: Source: Study Method : Investigative filming of kids over time. Credentials: Excellent

Inhibition of RAS activation due to a homozygous ezrin variant in patients with profound intellectual disability.

PubMed

Riecken, Lars Björn; Tawamie, Hasan; Dornblut, Carsten; Buchert, Rebecca; Ismayel, Amina; Schulz, Alexander; Schumacher, Johannes; Sticht, Heinrich; Pohl, Katja J; Cui, Yan; Reis, André; Morrison, Helen; Abou Jamra, Rami

2015-02-01

Gain-of-function alterations in several components and modulators of the Ras-MAPK pathway lead to dysregulation of the pathway and cause a broad spectrum of autosomal dominant developmental disorders, collectively known as RASopathies. These findings demonstrate the importance of tight multilevel Ras regulation to safeguard signaling output and prevent aberrant activity. We have recently identified ezrin as a novel regulatory element required for Ras activation. Homozygosity mapping and exome sequencing have now revealed the first presumably disease-causing variant in the coding gene EZR in two siblings with a profound intellectual disability. Localization and membrane targeting of the altered ezrin protein appeared normal but molecular modeling suggested protein interaction surfaces to be disturbed. Functional analysis revealed that the altered ezrin protein is no longer able to bind Ras and facilitate its activation. Furthermore, expression of the altered ezrin protein in different cell lines resulted in abnormal cellular processes, including reduced proliferation and neuritogenesis, thus revealing a possible mechanism for its phenotype in humans. To our knowledge, this is the first report of an autosomal recessively inherited loss-of-function mutation causing reduced Ras activity and thus extends and complements the pathogenicity spectrum of known Ras-MAPK pathway disturbances. © 2014 WILEY PERIODICALS, INC.

Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation.

PubMed

Støve, Svein Isungset; Magin, Robert S; Foyn, Håvard; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas

2016-07-06

N-Terminal acetylation is a common and important protein modification catalyzed by N-terminal acetyltransferases (NATs). Six human NATs (NatA-NatF) contain one catalytic subunit each, Naa10 to Naa60, respectively. In contrast to the ribosome-associated NatA to NatE, NatF/Naa60 specifically associates with Golgi membranes and acetylates transmembrane proteins. To gain insight into the molecular basis for the function of Naa60, we developed an Naa60 bisubstrate CoA-peptide conjugate inhibitor, determined its X-ray structure when bound to CoA and inhibitor, and carried out biochemical experiments. We show that Naa60 adapts an overall fold similar to that of the catalytic subunits of ribosome-associated NATs, but with the addition of two novel elongated loops that play important roles in substrate-specific binding. One of these loops mediates a dimer to monomer transition upon substrate-specific binding. Naa60 employs a catalytic mechanism most similar to Naa50. Collectively, these data reveal the molecular basis for Naa60-specific acetyltransferase activity with implications for its Golgi-specific functions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Network motif frequency vectors reveal evolving metabolic network organisation.

PubMed

Pearcy, Nicole; Crofts, Jonathan J; Chuzhanova, Nadia

2015-01-01

At the systems level many organisms of interest may be described by their patterns of interaction, and as such, are perhaps best characterised via network or graph models. Metabolic networks, in particular, are fundamental to the proper functioning of many important biological processes, and thus, have been widely studied over the past decade or so. Such investigations have revealed a number of shared topological features, such as a short characteristic path-length, large clustering coefficient and hierarchical modular structure. However, the extent to which evolutionary and functional properties of metabolism manifest via this underlying network architecture remains unclear. In this paper, we employ a novel graph embedding technique, based upon low-order network motifs, to compare metabolic network structure for 383 bacterial species categorised according to a number of biological features. In particular, we introduce a new global significance score which enables us to quantify important evolutionary relationships that exist between organisms and their physical environments. Using this new approach, we demonstrate a number of significant correlations between environmental factors, such as growth conditions and habitat variability, and network motif structure, providing evidence that organism adaptability leads to increased complexities in the resultant metabolic networks.

Crystal Structures of RMI1 and RMI2, Two OB-Fold Regulatory Subunits of the BLM Complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Feng; Yang, Yuting; Singh, Thiyam Ramsing

Mutations in BLM, a RecQ-like helicase, are linked to the autosomal recessive cancer-prone disorder Bloom's syndrome. BLM associates with topoisomerase (Topo) III{alpha}, RMI1, and RMI2 to form the BLM complex that is essential for genome stability. The RMI1-RMI2 heterodimer stimulates the dissolution of double Holliday junction into non-crossover recombinants mediated by BLM-Topo III{alpha} and is essential for stabilizing the BLM complex. However, the molecular basis of these functions of RMI1 and RMI2 remains unclear. Here we report the crystal structures of multiple domains of RMI1-RMI2, providing direct confirmation of the existence of three oligonucleotide/oligosaccharide binding (OB)-folds in RMI1-RMI2. Our structuralmore » and biochemical analyses revealed an unexpected insertion motif in RMI1N-OB, which is important for stimulating the dHJ dissolution. We also revealed the structural basis of the interaction between RMI1C-OB and RMI2-OB and demonstrated the functional importance of the RMI1-RMI2 interaction in genome stability maintenance.« less

Variability in community functioning of mothers with serious mental illness.

PubMed

Bybee, Deborah; Mowbray, Carol T; Oyserman, Daphna; Lewandowski, Lisa

2003-01-01

In the post-deinstitutionalization era, everyday community functioning is an important aspect of assessment and treatment of individuals with serious mental illness. The current study focuses on correlates of community functioning among 332 low-income mothers with serious mental illness. Results revealed significant relationships between everyday functioning and a number of demographic, psychiatric, contextual, and mental health treatment variables. Current psychiatric symptoms accounted for the greatest amount of variance and completely mediated the effects of diagnosis and substance abuse history on community functioning; yet contextual variables such as financial worries and social support were also significant predictors, even after controlling for symptoms and other clinical characteristics. Additionally, use of mental health services was a significant moderator of the effect of social stress on community functioning. Implications of results for future research and practice are discussed.

Family Functioning and Adolescent Psychological Maladjustment: The Mediating Role of Coping Strategies.

PubMed

Francisco, Rita; Loios, Sara; Pedro, Marta

2016-10-01

This study aims to analyze the mediating role of coping strategies in the relationship between family functioning and youth maladjustment. A community sample of 341 adolescents (M = 15.11 years old; SD = 1.71) completed self-report measures about such variables. Results showed that a perception of an inadequate family functioning was associated with the use of maladaptive coping strategies, as well as with youth psychological maladjustment. The results also revealed that rumination and support-seeking mediated the relationship between family functioning and internalizing behavior, and hostile expression of feelings played a mediating role between family functioning and externalizing behavior. No gender differences were found in the relationship between variables. This study emphasizes the importance of coping strategies used by adolescents to understand the relationship between family functioning and youth psychological maladjustment.

Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

PubMed Central

2015-01-01

We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals. PMID:24918484

Circular RNAs: analysis, expression and potential functions

PubMed Central

Salzman, Julia

2016-01-01

Just a few years ago, it had been assumed that the dominant RNA isoforms produced from eukaryotic genes were variants of messenger RNA, functioning as intermediates in gene expression. In early 2012, however, a surprising discovery was made: circular RNA (circRNA) was shown to be a transcriptional product in thousands of human and mouse genes and in hundreds of cases constituted the dominant RNA isoform. Subsequent studies revealed that the expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across the eukaryotic tree of life. These features suggest important functions for these molecules. Here, we describe major advances in the field of circRNA biology, focusing on the regulation of and functional roles played by these molecules. PMID:27246710

A rho-binding protein kinase C-like activity is required for the function of protein kinase N in Drosophila development.

PubMed

Betson, Martha; Settleman, Jeffrey

2007-08-01

The Rho GTPases interact with multiple downstream effectors to exert their biological functions, which include important roles in tissue morphogenesis during the development of multicellular organisms. Among the Rho effectors are the protein kinase N (PKN) proteins, which are protein kinase C (PKC)-like kinases that bind activated Rho GTPases. The PKN proteins are well conserved evolutionarily, but their biological role in any organism is poorly understood. We previously determined that the single Drosophila ortholog of mammalian PKN proteins, Pkn, is a Rho/Rac-binding kinase essential for Drosophila development. By performing "rescue" studies with various Pkn mutant constructs, we have defined the domains of Pkn required for its role during Drosophila development. These studies suggested that Rho, but not Rac binding is important for Pkn function in development. In addition, we determined that the kinase domain of PKC53E, a PKC family kinase, can functionally substitute for the kinase domain of Pkn during development, thereby exemplifying the evolutionary strategy of "combining" functional domains to produce proteins with distinct biological activities. Interestingly, we also identified a requirement for Pkn in wing morphogenesis, thereby revealing the first postembryonic function for Pkn.

Arabidopsis fhl/fhy1 double mutant reveals a distinct cytoplasmic action of phytochrome A

PubMed Central

Rösler, Jutta; Klein, Ilse; Zeidler, Mathias

2007-01-01

Phytochrome A (phyA) plays an important role during germination and early seedling development. Because phyA is the primary photoreceptor for the high-irradiance response and the very-low-fluence response, it can trigger development not only in red and far-red (FR) light but also in a wider range of light qualities. Although phyA action is generally associated with translocation to the nucleus and regulation of transcription, there is evidence for additional cytoplasmic functions. Because nuclear accumulation of phyA has been shown to depend on far-red-elongated hypocotyl 1 (FHY1) and FHL (FHY1-like), investigation of phyA function in a double fhl/fhy1 mutant might be valuable in revealing the mechanism of phyA translocation and possible cytoplasmic functions. In fhl/fhy1, the FR-triggered nuclear translocation of phyA could no longer be detected but could be restored by transgenic expression of CFP:FHY1. Whereas the fhl/fhy1 mutant showed a phyA phenotype in respect to hypocotyl elongation and cotyledon opening under high-irradiance response conditions as well as a typical phyA germination phenotype under very-low-fluence response conditions, fhl/fhy1 showed no phenotype with respect to the phyA-dependent abrogation of negative gravitropism in blue light and in red-enhanced phototropism, demonstrating clear cytoplasmic functions of phyA. Disturbance of phyA nuclear import in fhl/fhy1 led to formation of FR-induced phyA:GFP cytoplasmic foci resembling the sequestered areas of phytochrome. FHY1 and FHL play crucial roles in phyA nuclear translocation and signaling. Thus the double-mutant fhl/fhy1 allows nuclear and cytoplasmic phyA functions to be separated, leading to the novel identification of cytoplasmic phyA responses. PMID:17566111

Common and Dissociable Neural Activity After Mindfulness-Based Stress Reduction and Relaxation Response Programs.

PubMed

Sevinc, Gunes; Hölzel, Britta K; Hashmi, Javeria; Greenberg, Jonathan; McCallister, Adrienne; Treadway, Michael; Schneider, Marissa L; Dusek, Jeffery A; Carmody, James; Lazar, Sara W

2018-06-01

We investigated common and dissociable neural and psychological correlates of two widely used meditation-based stress reduction programs. Participants were randomized to the Relaxation Response (RR; n = 18; 56% female) or the Mindfulness-Based Stress Reduction (MBSR; n = 16; 56% female) programs. Both programs use a "bodyscan" meditation; however, the RR program explicitly emphasizes physical relaxation during this practice, whereas the MBSR program emphasizes mindful awareness with no explicit relaxation instructions. After the programs, neural activity during the respective meditation was investigated using functional magnetic resonance imaging. Both programs were associated with reduced stress (for RR, from 14.1 ± 6.6 to 11.3 ± 5.5 [Cohen's d = 0.50; for MBSR, from 17.7 ± 5.7 to 11.9 ± 5.0 [Cohen's d = 1.02]). Conjunction analyses revealed functional coupling between ventromedial prefrontal regions and supplementary motor areas (p < .001). The disjunction analysis indicated that the RR bodyscan was associated with stronger functional connectivity of the right inferior frontal gyrus-an important hub of intentional inhibition and control-with supplementary motor areas (p < .001, family-wise error [FWE] rate corrected). The MBSR program was uniquely associated with improvements in self-compassion and rumination, and the within-group analysis of MBSR bodyscan revealed significant functional connectivity of the right anterior insula-an important hub of sensory awareness and salience-with pregenual anterior cingulate during bodyscan meditation compared with rest (p = .03, FWE corrected). The bodyscan exercises in each program were associated with both overlapping and differential functional coupling patterns, which were consistent with each program's theoretical foundation. These results may have implications for the differential effects of these programs for the treatment of diverse conditions.

Comparison of S. cerevisiae F-BAR domain structures reveals a conserved inositol phosphate binding site

PubMed Central

Moravcevic, Katarina; Alvarado, Diego; Schmitz, Karl R.; Kenniston, Jon A.; Mendrola, Jeannine M.; Ferguson, Kathryn M.; Lemmon, Mark A.

2015-01-01

SUMMARY F-BAR domains control membrane interactions in endocytosis, cytokinesis, and cell signaling. Although generally thought to bind curved membranes containing negatively charged phospholipids, numerous functional studies argue that differences in lipid-binding selectivities of F-BAR domains are functionally important. Here, we compare membrane-binding properties of the S. cerevisiae F-BAR domains in vitro and in vivo. Whereas some F-BAR domains (such as Bzz1p and Hof1p F-BARs) bind equally well to all phospholipids, the F-BAR domain from the RhoGAP Rgd1p preferentially binds phosphoinositides. We determined X-ray crystal structures of F-BAR domains from Hof1p and Rgd1p, the latter bound to an inositol phosphate. The structures explain phospholipid-binding selectivity differences, and reveal an F-BAR phosphoinositide binding site that is fully conserved in a mammalian RhoGAP called Gmip, and is partly retained in certain other F-BAR domains. Our findings reveal previously unappreciated determinants of F-BAR domain lipid-binding specificity, and provide a basis for its prediction from sequence. PMID:25620000

A guide to large-scale RNA sample preparation.

PubMed

Baronti, Lorenzo; Karlsson, Hampus; Marušič, Maja; Petzold, Katja

2018-05-01

RNA is becoming more important as an increasing number of functions, both regulatory and enzymatic, are being discovered on a daily basis. As the RNA boom has just begun, most techniques are still in development and changes occur frequently. To understand RNA functions, revealing the structure of RNA is of utmost importance, which requires sample preparation. We review the latest methods to produce and purify a variation of RNA molecules for different purposes with the main focus on structural biology and biophysics. We present a guide aimed at identifying the most suitable method for your RNA and your biological question and highlighting the advantages of different methods. Graphical abstract In this review we present different methods for large-scale production and purification of RNAs for structural and biophysical studies.

Phosphoenolpyruvate carboxylase: a new era of structural biology.

PubMed

Izui, Katsura; Matsumura, Hiroyoshi; Furumoto, Tsuyoshi; Kai, Yasushi

2004-01-01

There have been remarkable advances in our knowledge of this important enzyme in the last decade. This review focuses on three recent topics: the three-dimensional structure of the protein, molecular mechanisms of catalytic and regulatory functions, and the molecular cloning and characterization of PEPC kinases, which are Ser/Thr kinases involved specifically in regulatory phosphorylation of vascular plant PEPC. Analysis by X-ray crystallography and site-directed mutagenesis for E. coli and maize PEPC identified the catalytic site and allosteric effector binding sites, and revealed the functional importance of mobile loops. We present the reaction mechanism of PEPC in which we assign the roles of individual amino acid residues. We discuss the unique molecular property of PEPC kinase and its possible regulation at the post-translational level.

Functional Relationships for Investigating Cognitive Processes

PubMed Central

Wright, Anthony A.

2013-01-01

Functional relationships (from systematic manipulation of critical variables) are advocated for revealing fundamental processes of (comparative) cognition—through examples from my work in psychophysics, learning, and memory. Functional relationships for pigeon wavelength (hue) discrimination revealed best discrimination at the spectral points of hue transition for pigeons—a correspondence (i.e., functional relationship) similar to that for humans. Functional relationships for learning revealed: Item-specific or relational learning in matching to sample as a function of the pigeons’ sample-response requirement, and same/different abstract-concept learning as a function of the training set size for rhesus monkeys, capuchin monkeys, and pigeons. Functional relationships for visual memory revealed serial position functions (a 1st order functional relationship) that changed systematically with retention delay (a 2nd order relationship) for pigeons, capuchin monkeys, rhesus monkeys, and humans. Functional relationships for rhesus-monkey auditory memory also revealed systematic changes in serial position functions with delay, but these changes were opposite to those for visual memory. Functional relationships for proactive interference revealed interference that varied as a function of a ratio of delay times. Functional relationships for change detection memory revealed (qualitative) similarities and (quantitative) differences in human and monkey visual short term memory as a function of the number of memory items. It is concluded that these findings were made possible by varying critical variables over a substantial portion of the manipulable range to generate functions and derive relationships. PMID:23174335

Development of large-scale functional brain networks in children.

PubMed

Supekar, Kaustubh; Musen, Mark; Menon, Vinod

2009-07-01

The ontogeny of large-scale functional organization of the human brain is not well understood. Here we use network analysis of intrinsic functional connectivity to characterize the organization of brain networks in 23 children (ages 7-9 y) and 22 young-adults (ages 19-22 y). Comparison of network properties, including path-length, clustering-coefficient, hierarchy, and regional connectivity, revealed that although children and young-adults' brains have similar "small-world" organization at the global level, they differ significantly in hierarchical organization and interregional connectivity. We found that subcortical areas were more strongly connected with primary sensory, association, and paralimbic areas in children, whereas young-adults showed stronger cortico-cortical connectivity between paralimbic, limbic, and association areas. Further, combined analysis of functional connectivity with wiring distance measures derived from white-matter fiber tracking revealed that the development of large-scale brain networks is characterized by weakening of short-range functional connectivity and strengthening of long-range functional connectivity. Importantly, our findings show that the dynamic process of over-connectivity followed by pruning, which rewires connectivity at the neuronal level, also operates at the systems level, helping to reconfigure and rebalance subcortical and paralimbic connectivity in the developing brain. Our study demonstrates the usefulness of network analysis of brain connectivity to elucidate key principles underlying functional brain maturation, paving the way for novel studies of disrupted brain connectivity in neurodevelopmental disorders such as autism.

Development of Large-Scale Functional Brain Networks in Children

PubMed Central

Supekar, Kaustubh; Musen, Mark; Menon, Vinod

2009-01-01

The ontogeny of large-scale functional organization of the human brain is not well understood. Here we use network analysis of intrinsic functional connectivity to characterize the organization of brain networks in 23 children (ages 7–9 y) and 22 young-adults (ages 19–22 y). Comparison of network properties, including path-length, clustering-coefficient, hierarchy, and regional connectivity, revealed that although children and young-adults' brains have similar “small-world” organization at the global level, they differ significantly in hierarchical organization and interregional connectivity. We found that subcortical areas were more strongly connected with primary sensory, association, and paralimbic areas in children, whereas young-adults showed stronger cortico-cortical connectivity between paralimbic, limbic, and association areas. Further, combined analysis of functional connectivity with wiring distance measures derived from white-matter fiber tracking revealed that the development of large-scale brain networks is characterized by weakening of short-range functional connectivity and strengthening of long-range functional connectivity. Importantly, our findings show that the dynamic process of over-connectivity followed by pruning, which rewires connectivity at the neuronal level, also operates at the systems level, helping to reconfigure and rebalance subcortical and paralimbic connectivity in the developing brain. Our study demonstrates the usefulness of network analysis of brain connectivity to elucidate key principles underlying functional brain maturation, paving the way for novel studies of disrupted brain connectivity in neurodevelopmental disorders such as autism. PMID:19621066

Evidence for Conformationa1 Heterogeneity of Fission Protein Fis1 from Saccharomyces cerevisiae†

PubMed Central

Picton, Lora K.; Casares, Salvador; Monahan, Ann C.; Majumdar, Ananya; Hill, R. Blake

2009-01-01

Fission 1 (Fis1) is an evolutionarily conserved, type II integral membrane protein implicated in maintaining the proper morphology of mitochondria and peroxisomes. A concave surface on the cytosolic domain of Fis1 from Saccharomyces cerevisiae is implicated in binding other fission proteins, yet structural studies reveal that this surface is sterically occluded by its N-terminal arm. Here we address the question of whether the N-terminal arm of yeast Fis1 exists in a dynamic equilibrium that would allow access to this functionally important surface. NMR measurements sensitive to dynamics occurring on a wide range of time scales (picoseconds to minutes) were used to assess whether the Fis1 arm is dynamic. Hydrogen–deuterium exchange experiments revealed that the Fis1 arm, α-helix 6, and proximal loops were not protected from solvent exchange, consistent with motions on the second to minute time scale. An engineered cysteine, I85C, located on the concave surface that lies underneath the Fis1 arm, was readily modified by a fluorescent probe, revealing more solvent accessibility of this position than would be predicted from the structure. Chemical denaturation, NMR chemical shift perturbation, and residual dipolar coupling experiments support the idea that the dynamic equilibrium can be shifted on the basis of changing pH and temperature, with the changes primarily localizing to the Fis1 arm and proximal regions. The data as a whole are consistent with the Fis1 arm adopting a primarily “closed” conformational state able to undergo dynamic excursions that reveal the concave surface and therefore may be important for binding other fission factors and for Fis1 function. PMID:19522466

Peroxisome protein import: a complex journey.

PubMed

Baker, Alison; Lanyon-Hogg, Thomas; Warriner, Stuart L

2016-06-15

The import of proteins into peroxisomes possesses many unusual features such as the ability to import folded proteins, and a surprising diversity of targeting signals with differing affinities that can be recognized by the same receptor. As understanding of the structure and function of many components of the protein import machinery has grown, an increasingly complex network of factors affecting each step of the import pathway has emerged. Structural studies have revealed the presence of additional interactions between cargo proteins and the PEX5 receptor that affect import potential, with a subtle network of cargo-induced conformational changes in PEX5 being involved in the import process. Biochemical studies have also indicated an interdependence of receptor-cargo import with release of unloaded receptor from the peroxisome. Here, we provide an update on recent literature concerning mechanisms of protein import into peroxisomes. © 2016 The Author(s).

Discovering functional DNA elements using population genomic information: a proof of concept using human mtDNA.

PubMed

Schrider, Daniel R; Kern, Andrew D

2014-06-09

Identifying the complete set of functional elements within the human genome would be a windfall for multiple areas of biological research including medicine, molecular biology, and evolution. Complete knowledge of function would aid in the prioritization of loci when searching for the genetic bases of disease or adaptive phenotypes. Because mutations that disrupt function are disfavored by natural selection, purifying selection leaves a detectable signature within functional elements; accordingly, this signal has been exploited for over a decade through the use of genomic comparisons of distantly related species. While this is so, the functional complement of the genome changes extensively across time and between lineages; therefore, evidence of the current action of purifying selection in humans is essential. Because the removal of deleterious mutations by natural selection also reduces within-species genetic diversity within functional loci, dense population genetic data have the potential to reveal genomic elements that are currently functional. Here, we assess the potential of this approach by examining an ultradeep sample of human mitochondrial genomes (n = 16,411). We show that the high density of polymorphism in this data set precisely delineates regions experiencing purifying selection. Furthermore, we show that the number of segregating alleles at a site is strongly correlated with its divergence across species after accounting for known mutational biases in human mitochondrial DNA (ρ = 0.51; P < 2.2 × 10(-16)). These two measures track one another at a remarkably fine scale across many loci-a correlation that is purely the result of natural selection. Our results demonstrate that genetic variation has the potential to reveal with surprising precision which regions in the genome are currently performing important functions and likely to have deleterious fitness effects when mutated. As more complete human genomes are sequenced, similar power to reveal purifying selection may be achievable in the human nuclear genome. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Metabolomics reveals mycoplasma contamination interferes with the metabolism of PANC-1 cells.

PubMed

Yu, Tao; Wang, Yongtao; Zhang, Huizhen; Johnson, Caroline H; Jiang, Yiming; Li, Xiangjun; Wu, Zeming; Liu, Tian; Krausz, Kristopher W; Yu, Aiming; Gonzalez, Frank J; Huang, Min; Bi, Huichang

2016-06-01

Mycoplasma contamination is a common problem in cell culture and can alter cellular functions. Since cell metabolism is either directly or indirectly involved in every aspect of cell function, it is important to detect changes to the cellular metabolome after mycoplasma infection. In this study, liquid chromatography mass spectrometry (LC/MS)-based metabolomics was used to investigate the effect of mycoplasma contamination on the cellular metabolism of human pancreatic carcinoma cells (PANC-1). Multivariate analysis demonstrated that mycoplasma contamination induced significant metabolic changes in PANC-1 cells. Twenty-three metabolites were identified and found to be involved in arginine and purine metabolism and energy supply. This study demonstrates that mycoplasma contamination significantly alters cellular metabolite levels, confirming the compelling need for routine checking of cell cultures for mycoplasma contamination, particularly when used for metabolomics studies. Graphical abstract Metabolomics reveals mycoplasma contamination changes the metabolome of PANC-1 cells.

Conceptual study of future spacecraft systems, part C

NASA Astrophysics Data System (ADS)

1993-10-01

This report describes observation and collection of debris and a test satellite of the electric orbit transfer vehicle (OTV). The debris observation and collection is important for safety of in-orbit spacecraft. Since ground observation is limited in determination of the size and altitude of debris, the use of satellites was proposed to observe and collect debris. In the basic conceptual study, such satellites should have the following functions: to deorbit debris by vaporization using laser gun, to observe electric wave of debris, and to collect and deorbit debris. The electric OTV requires the following functions: to place stationary satellites in orbit, to deorbit useless satellites, to collect failed satellites, to exchange failed components, to supply expendables, and to change satellite configuration. The mission and system of electric OTV in the engineering test satellite (ETS) was reviewed to reveal necessary in-orbit experiments for verification of electric OTV and to reveal outline of the satellite system.

Revealing Abrupt and Spontaneous Ruptures of Protein Native Structure under picoNewton Compressive Force Manipulation.

PubMed

Chowdhury, S Roy; Cao, Jin; He, Yufan; Lu, H Peter

2018-03-27

Manipulating protein conformations for exploring protein structure-function relationship has shown great promise. Although protein conformational changes under pulling force manipulation have been extensively studied, protein conformation changes under a compressive force have not been explored quantitatively. The latter is even more biologically significant and relevant in revealing protein functions in living cells associated with protein crowdedness, distribution fluctuations, and cell osmotic stress. Here we report our experimental observations on abrupt ruptures of protein native structures under compressive force, demonstrated and studied by single-molecule AFM-FRET spectroscopic nanoscopy. Our results show that the protein ruptures are abrupt and spontaneous events occurred when the compressive force reaches a threshold of 12-75 pN, a force amplitude accessible from thermal fluctuations in a living cell. The abrupt ruptures are sensitive to local environment, likely a general and important pathway of protein unfolding in living cells.

Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics.

PubMed

Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M; Abel, Steven M; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S; Hansen, Scott D; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K; Kuriyan, John; Groves, Jay T

2014-07-04

Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. Copyright © 2014, American Association for the Advancement of Science.

PHOTOSYNTHESIS. A 12 Å carotenoid translocation in a photoswitch associated with cyanobacterial photoprotection.

PubMed

Leverenz, Ryan L; Sutter, Markus; Wilson, Adjélé; Gupta, Sayan; Thurotte, Adrien; Bourcier de Carbon, Céline; Petzold, Christopher J; Ralston, Corie; Perreau, François; Kirilovsky, Diana; Kerfeld, Cheryl A

2015-06-26

Pigment-protein and pigment-pigment interactions are of fundamental importance to the light-harvesting and photoprotective functions essential to oxygenic photosynthesis. The orange carotenoid protein (OCP) functions as both a sensor of light and effector of photoprotective energy dissipation in cyanobacteria. We report the atomic-resolution structure of an active form of the OCP consisting of the N-terminal domain and a single noncovalently bound carotenoid pigment. The crystal structure, combined with additional solution-state structural data, reveals that OCP photoactivation is accompanied by a 12 angstrom translocation of the pigment within the protein and a reconfiguration of carotenoid-protein interactions. Our results identify the origin of the photochromic changes in the OCP triggered by light and reveal the structural determinants required for interaction with the light-harvesting antenna during photoprotection. Copyright © 2015, American Association for the Advancement of Science.

Investigations of optical and thermoelectric response of direct band gap Ca3XO (X = Si, Ge) anti-perovskites stabilized in cubic and orthorhombic phases

NASA Astrophysics Data System (ADS)

Mahmood, Q.; Ashraf, A.; Hassan, M.

2018-02-01

We predict the phase dependent electronic properties for elaborating the optical and thermoelectric behaviors of both cubic (Pm-3m) and orthorhombic (Pbnm) Ca3XO (X = Si, Ge) antiperovskites using first-principles density functional theory (DFT) computations. The mBJ functional is employed for computing the most accurate electronic characteristics. A direct band gap semiconducting nature has been found appearing due to hybridization between O and Si/Ge p-states. The calculated band gaps lying in the infrared energy region suggest that the studied anti-perovskites can absorb visible and ultraviolet energy revealing potential optoelectronics device applications. Moreover, the important thermoelectric parameters are computed for illustrating the potential thermoelectric applications. Hence, the studied anti-perovskites can simultaneously exhibit various flexible material properties, which reveal their worth for the devices demonstrating versatile characteristics.

Escherichia coli type III secretion system 2: a new kind of T3SS?

PubMed

Zhou, Mingxu; Guo, Zhiyan; Duan, Qiangde; Hardwidge, Philip R; Zhu, Guoqiang

2014-03-19

Type III secretion systems (T3SSs) are employed by Gram-negative bacteria to deliver effector proteins into the cytoplasm of infected host cells. Enteropathogenic Escherichia coli use a T3SS to deliver effector proteins that result in the creation of the attaching and effacing lesions. The genome sequence of the Escherichia coli pathotype O157:H7 revealed the existence of a gene cluster encoding components of a second type III secretion system, the E. coli type III secretion system 2 (ETT2). Researchers have revealed that, although ETT2 may not be a functional secretion system in most (or all) strains, it still plays an important role in bacterial virulence. This article summarizes current knowledge regarding the E. coli ETT2, including its genetic characteristics, prevalence, function, association with virulence, and prospects for future work.

Asy2/Mer2: an evolutionarily conserved mediator of meiotic recombination, pairing, and global chromosome compaction.

PubMed

Tessé, Sophie; Bourbon, Henri-Marc; Debuchy, Robert; Budin, Karine; Dubois, Emeline; Liangran, Zhang; Antoine, Romain; Piolot, Tristan; Kleckner, Nancy; Zickler, Denise; Espagne, Eric

2017-09-15

Meiosis is the cellular program by which a diploid cell gives rise to haploid gametes for sexual reproduction. Meiotic progression depends on tight physical and functional coupling of recombination steps at the DNA level with specific organizational features of meiotic-prophase chromosomes. The present study reveals that every step of this coupling is mediated by a single molecule: Asy2/Mer2. We show that Mer2, identified so far only in budding and fission yeasts, is in fact evolutionarily conserved from fungi (Mer2/Rec15/Asy2/Bad42) to plants (PRD3/PAIR1) and mammals (IHO1). In yeasts, Mer2 mediates assembly of recombination-initiation complexes and double-strand breaks (DSBs). This role is conserved in the fungus Sordaria However, functional analysis of 13 mer2 mutants and successive localization of Mer2 to axis, synaptonemal complex (SC), and chromatin revealed, in addition, three further important functions. First, after DSB formation, Mer2 is required for pairing by mediating homolog spatial juxtaposition, with implications for crossover (CO) patterning/interference. Second, Mer2 participates in the transfer/maintenance and release of recombination complexes to/from the SC central region. Third, after completion of recombination, potentially dependent on SUMOylation, Mer2 mediates global chromosome compaction and post-recombination chiasma development. Thus, beyond its role as a recombinosome-axis/SC linker molecule, Mer2 has important functions in relation to basic chromosome structure. © 2017 Tessé et al.; Published by Cold Spring Harbor Laboratory Press.

The low density lipoprotein receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies

PubMed Central

Lillis, Anna P.; Van Duyn, Lauren B.; Murphy-Ullrich, Joanne E.; Strickland, Dudley K.

2008-01-01

The low-density lipoprotein (LDL) receptor-related protein (originally called LRP, but now referred to as LRP1) is a large endocytic receptor that is widely expressed in several tissues. LRP1 is a member of the LDL receptor family that plays diverse roles in various biological processes including lipoprotein metabolism, degradation of proteases, activation of lysosomal enzymes and cellular entry of bacterial toxins and viruses. Deletion of the LRP1 gene leads to lethality in mice, revealing a critical, but as of yet, undefined role in development. Tissue-specific gene deletion studies reveal an important contribution of LRP1 in the vasculature, central nervous system, in macrophages and in adipocytes. Three important properties of LRP1 dictate its diverse role in physiology: first, its ability to recognize more than thirty distinct ligands; second, its ability to bind a large number of cytoplasmic adaptor proteins via determinants located on its cytoplasmic domain in a phosphorylation-specific manner; and third, its ability to associate with and modulate the activity of other transmembrane receptors such as integrins and receptor tyrosine kinases. PMID:18626063

Effect of roughage on rumen microbiota composition in the efficient feed converter and sturdy Indian Jaffrabadi buffalo (Bubalus bubalis).

PubMed

Nathani, Neelam M; Patel, Amrutlal K; Mootapally, Chandra Shekar; Reddy, Bhaskar; Shah, Shailesh V; Lunagaria, Pravin M; Kothari, Ramesh K; Joshi, Chaitanya G

2015-12-29

The rumen microbiota functions as an effective system for conversion of dietary feed to microbial proteins and volatile fatty acids. In the present study, metagenomic approach was applied to elucidate the buffalo rumen microbiome of Jaffrabadi buffalo adapted to varied dietary treatments with the hypothesis that the microbial diversity and subsequent in the functional capacity will alter with diet change and enhance our knowledge of effect of microbe on host physiology. Eight adult animals were gradually adapted to an increasing roughage diet (4 animals each with green and dry roughage) containing 50:50 (J1), 75:25 (J2) and 100:0 (J3) roughage to concentrate proportion for 6 weeks. Metagenomic sequences of solid (fiber adherent microbiota) and liquid (fiber free microbiota) fractions obtained using Ion Torrent PGM platform were analyzed using MG-RAST server and CAZymes approach. Taxonomic analysis revealed that Bacteroidetes was the most abundant phylum followed by Firmicutes, Fibrobacter and Proteobacteria. Functional analysis revealed protein (25-30 %) and carbohydrate (15-20 %) metabolism as the dominant categories. Principal component analysis demonstrated that roughage proportion, fraction of rumen and type of forage affected rumen microbiome at taxonomic as well as functional level. Rumen metabolite study revealed that rumen fluid nitrogen content reduced in high roughage diet fed animals and pathway analysis showed reduction in the genes coding enzymes involved in methanogenesis pathway. CAZyme annotation revealed the abundance of genes encoding glycoside hydrolases (GH), with the GH3 family most abundant followed by GH2 and GH13 in all samples. Results reveals that high roughage diet feed improved microbial protein synthesis and reduces methane emission. CAZyme analysis indicated the importance of microbiome in feed component digestion for fulfilling energy requirements of the host. The findings help determine the role of rumen microbes in plant polysaccharide breakdown and in developing strategies to maximize productivity in ruminants.

Mineral and organic growing media have distinct community structure, stability and functionality in soilless culture systems.

PubMed

Grunert, Oliver; Hernandez-Sanabria, Emma; Vilchez-Vargas, Ramiro; Jauregui, Ruy; Pieper, Dietmar H; Perneel, Maaike; Van Labeke, Marie-Christine; Reheul, Dirk; Boon, Nico

2016-01-05

The choice of soilless growing medium for plant nutrition, growth and support is crucial for improving the eco-sustainability of the production in horticultural systems. As our current understanding of the functional microbial communities inhabiting this ecosystem is still limited, we examined the microbial community development of the two most important growing media (organic and mineral) used in open soilless horticultural systems. We aimed to identify factors that influence community composition over time, and to compare the distribution of individual taxa across growing media, and their potential functionality. High throughput sequencing analysis revealed a distinctive and stable microbial community in the organic growing medium. Humidity, pH, nitrate-N, ammonium-N and conductivity were uncovered as the main factors associated with the resident bacterial communities. Ammonium-N was correlated with Rhizobiaceae abundance, while potential competitive interactions among both Methylophilaceae and Actinobacteridae with Rhizobiaceae were suggested. Our results revealed that soilless growing media are unique niches for diverse bacterial communities with temporal functional stability, which may possibly impact the resistance to external forces. These differences in communities can be used to develop strategies to move towards a sustainable horticulture with increased productivity and quality.

Astrocytes express functional TRPV2 ion channels.

PubMed

Shibasaki, Koji; Ishizaki, Yasuki; Mandadi, Sravan

2013-11-15

Thermosensitive transient receptor potential (thermo TRP) channels are important for sensory transduction. Among them, TRPV2 has an interesting characteristic of being activated by very high temperature (>52 °C). In addition to the heat sensor function, TRPV2 also acts as a mechanosensor, an osomosensor and a lipid sensor. It has been reported that TRPV2 is expressed in heart, intestine, pancreas and sensory nerves. In the central nervous system, neuronal TRPV2 expression was reported, however, glial expression and the precise roles of TRPV2 have not been determined. To explore the functional expression of TRPV2 in astrocytes, the expression was determined by histological and physiological methods. Interestingly, TRPV2 expression was detected in plasma membrane of astrocytes, and the astrocytic TRPV2 was activated by very high temperature (>50 °C) consistent with the reported characteristic. We revealed that the astrocytic TRPV2 was also activated by lysophosphatidylcholine, a known endogenous lipid ligand for TRPV2, suggesting that astrocytic TRPV2 might regulate neuronal activities in response to lipid metabolism. Thus, for the first time we revealed that TRPV2 is functionally expressed in astrocytes in addition to neurons. Copyright © 2013 Elsevier Inc. All rights reserved.

A functional analysis of the spacer of V(D)J recombination signal sequences.

PubMed

Lee, Alfred Ian; Fugmann, Sebastian D; Cowell, Lindsay G; Ptaszek, Leon M; Kelsoe, Garnett; Schatz, David G

2003-10-01

During lymphocyte development, V(D)J recombination assembles antigen receptor genes from component V, D, and J gene segments. These gene segments are flanked by a recombination signal sequence (RSS), which serves as the binding site for the recombination machinery. The murine Jbeta2.6 gene segment is a recombinationally inactive pseudogene, but examination of its RSS reveals no obvious reason for its failure to recombine. Mutagenesis of the Jbeta2.6 RSS demonstrates that the sequences of the heptamer, nonamer, and spacer are all important. Strikingly, changes solely in the spacer sequence can result in dramatic differences in the level of recombination. The subsequent analysis of a library of more than 4,000 spacer variants revealed that spacer residues of particular functional importance are correlated with their degree of conservation. Biochemical assays indicate distinct cooperation between the spacer and heptamer/nonamer along each step of the reaction pathway. The results suggest that the spacer serves not only to ensure the appropriate distance between the heptamer and nonamer but also regulates RSS activity by providing additional RAG:RSS interaction surfaces. We conclude that while RSSs are defined by a "digital" requirement for absolutely conserved nucleotides, the quality of RSS function is determined in an "analog" manner by numerous complex interactions between the RAG proteins and the less-well conserved nucleotides in the heptamer, the nonamer, and, importantly, the spacer. Those modulatory effects are accurately predicted by a new computational algorithm for "RSS information content." The interplay between such binary and multiplicative modes of interactions provides a general model for analyzing protein-DNA interactions in various biological systems.

Quantitative flux analysis reveals folate-dependent NADPH production

NASA Astrophysics Data System (ADS)

Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J.; Shlomi, Tomer; Thompson, Craig B.; Rabinowitz, Joshua D.

2014-06-01

ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP+ to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP+ and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power.

Genome-wide classification, evolutionary analysis and gene expression patterns of the kinome in Gossypium

PubMed Central

Yan, Jun; Li, Guilin; Guo, Xingqi; Li, Yang; Cao, Xuecheng

2018-01-01

The protein kinase (PK, kinome) family is one of the largest families in plants and regulates almost all aspects of plant processes, including plant development and stress responses. Despite their important functions, comprehensive functional classification, evolutionary analysis and expression patterns of the cotton PK gene family has yet to be performed on PK genes. In this study, we identified the cotton kinomes in the Gossypium raimondii, Gossypium arboretum, Gossypium hirsutum and Gossypium barbadense genomes and classified them into 7 groups and 122–24 subfamilies using software HMMER v3.0 scanning and neighbor-joining (NJ) phylogenetic analysis. Some conserved exon-intron structures were identified not only in cotton species but also in primitive plants, ferns and moss, suggesting the significant function and ancient origination of these PK genes. Collinearity analysis revealed that 16.6 million years ago (Mya) cotton-specific whole genome duplication (WGD) events may have played a partial role in the expansion of the cotton kinomes, whereas tandem duplication (TD) events mainly contributed to the expansion of the cotton RLK group. Synteny analysis revealed that tetraploidization of G. hirsutum and G. barbadense contributed to the expansion of G. hirsutum and G. barbadense PKs. Global expression analysis of cotton PKs revealed stress-specific and fiber development-related expression patterns, suggesting that many cotton PKs might be involved in the regulation of the stress response and fiber development processes. This study provides foundational information for further studies on the evolution and molecular function of cotton PKs. PMID:29768506

High-Throughput Analysis of Promoter Occupancy Reveals New Targets for Arx, a Gene Mutated in Mental Retardation and Interneuronopathies

PubMed Central

Quillé, Marie-Lise; Hirchaud, Edouard; Baron, Daniel; Benech, Caroline; Guihot, Jeanne; Placet, Morgane; Mignen, Olivier; Férec, Claude; Houlgatte, Rémi; Friocourt, Gaëlle

2011-01-01

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations. PMID:21966449

Evolutionary conservation of the polyproline II conformation surrounding intrinsically disordered phosphorylation sites.

PubMed

Elam, W Austin; Schrank, Travis P; Campagnolo, Andrew J; Hilser, Vincent J

2013-04-01

Intrinsically disordered (ID) proteins function in the absence of a unique stable structure and appear to challenge the classic structure-function paradigm. The extent to which ID proteins take advantage of subtle conformational biases to perform functions, and whether signals for such mechanism can be identified in proteome-wide studies is not well understood. Of particular interest is the polyproline II (PII) conformation, suggested to be highly populated in unfolded proteins. We experimentally determine a complete calorimetric propensity scale for the PII conformation. Projection of the scale into representative eukaryotic proteomes reveals significant PII bias in regions coding for ID proteins. Importantly, enrichment of PII in ID proteins, or protein segments, is also captured by other PII scales, indicating that this enrichment is robustly encoded and universally detectable regardless of the method of PII propensity determination. Gene ontology (GO) terms obtained using our PII scale and other scales demonstrate a consensus for molecular functions performed by high PII proteins across the proteome. Perhaps the most striking result of the GO analysis is conserved enrichment (P < 10(-8) ) of phosphorylation sites in high PII regions found by all PII scales. Subsequent conformational analysis reveals a phosphorylation-dependent modulation of PII, suggestive of a conserved "tunability" within these regions. In summary, the application of an experimentally determined polyproline II (PII) propensity scale to proteome-wide sequence analysis and gene ontology reveals an enrichment of PII bias near disordered phosphorylation sites that is conserved throughout eukaryotes. Copyright © 2013 The Protein Society.

The complex roles of space and environment in structuring functional, taxonomic and phylogenetic beta diversity of frogs in the Atlantic Forest

PubMed Central

Luiz, Amom Mendes; Sawaya, Ricardo J.

2018-01-01

Ecological communities are complex entities that can be maintained and structured by niche-based processes such as environmental conditions, and spatial processes such as dispersal. Thus, diversity patterns may be shaped simultaneously at different spatial scales by very distinct processes. Herein we assess whether and how functional, taxonomic, and phylogenetic beta diversities of frog tadpoles are explained by environmental and/or spatial predictors. We implemented a distance–based redundancy analysis to explore variation in components of beta diversity explained by pure environmental and pure spatial predictors, as well as their interactions, at both fine and broad spatial scales. Our results indicated important but complex roles of spatial and environmental predictors in structuring phylogenetic, taxonomic and functional beta diversities. The pure fine-scales spatial fraction was more important in structuring all beta diversity components, especially to functional and taxonomical spatial turnover. Environmental variables such as canopy cover and vegetation structure were important predictors of all components, but especially to functional and taxonomic beta diversity. We emphasize that distinct factors related to environment and space are affecting distinct components of beta diversity in different ways. Although weaker, phylogenetic beta diversity, which is structured more on biogeographical scales, and thus can be represented by spatially structured processes, was more related to broad spatial processes than other components. However, selected fine-scale spatial predictors denoted negative autocorrelation, which may be revealing the existence of differences in unmeasured habitat variables among samples. Although overall important, local environmental-based processes explained better functional and taxonomic beta diversity, as these diversity components carry an important ecological value. We highlight the importance of assessing different components of diversity patterns at different scales by spatially explicit models in order to improve our understanding of community structure and help to unravel the complex nature of biodiversity. PMID:29672575

Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line

PubMed Central

Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

2009-01-01

Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder.

PubMed

Rashid, Barnaly; Blanken, Laura M E; Muetzel, Ryan L; Miller, Robyn; Damaraju, Eswar; Arbabshirani, Mohammad R; Erhardt, Erik B; Verhulst, Frank C; van der Lugt, Aad; Jaddoe, Vincent W V; Tiemeier, Henning; White, Tonya; Calhoun, Vince

2018-03-30

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a "chronnectomic" (recurring, time-varying patterns of connectivity) approach to evaluate transient states of connectivity using resting-state functional MRI in a population-based sample of 774 6- to 10-year-old children. Dynamic connectivity was evaluated using a sliding-window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum. © 2018 Wiley Periodicals, Inc.

Ionospheric Outflow in the Magnetosphere: Circulation and Consequences

NASA Astrophysics Data System (ADS)

Welling, D. T.; Liemohn, M. W.

2017-12-01

Including ionospheric outflow in global magnetohydrodynamic models of near-Earth outer space has become an important step towards understanding the role of this plasma source in the magnetosphere. Such simulations have revealed the importance of outflow in populating the plasma sheet and inner magnetosphere as a function of outflow source characteristics. More importantly, these experiments have shown how outflow can control global dynamics, including tail dynamics and dayside reconnection rate. The broad impact of light and heavy ion outflow can create non-linear feedback loops between outflow and the magnetosphere. This paper reviews some of the most important revelations from global magnetospheric modeling that includes ionospheric outflow of light and heavy ions. It also introduces new advances in outflow modeling and coupling outflow to the magnetosphere.

The gut microbiome: Connecting spatial organization to function

PubMed Central

Tropini, Carolina; Earle, Kristen A.; Huang, Kerwyn Casey; Sonnenburg, Justin L.

2017-01-01

The first rudimentary evidence that the human body harbors a microbiota hinted at the complexity of host-associated microbial ecosystems. Now, almost 400 years later, a renaissance in the study of microbiota spatial organization, driven by coincident revolutions in imaging and sequencing technologies, is revealing functional relationships between biogeography and health, particularly in the vertebrate gut. In this review, we present our current understanding of principles governing the localization of intestinal bacteria, and spatial relationships between bacteria and their hosts. We further discuss important emerging directions that will enable progressing from the inherently descriptive nature of localization and –omics technologies to provide functional, quantitative, and mechanistic insight into this complex ecosystem. PMID:28407481

Wheat forecast economics effect study. [value of improved information on crop inventories, production, imports and exports

NASA Technical Reports Server (NTRS)

Mehra, R. K.; Rouhani, R.; Jones, S.; Schick, I.

1980-01-01

A model to assess the value of improved information regarding the inventories, productions, exports, and imports of crop on a worldwide basis is discussed. A previously proposed model is interpreted in a stochastic control setting and the underlying assumptions of the model are revealed. In solving the stochastic optimization problem, the Markov programming approach is much more powerful and exact as compared to the dynamic programming-simulation approach of the original model. The convergence of a dual variable Markov programming algorithm is shown to be fast and efficient. A computer program for the general model of multicountry-multiperiod is developed. As an example, the case of one country-two periods is treated and the results are presented in detail. A comparison with the original model results reveals certain interesting aspects of the algorithms and the dependence of the value of information on the incremental cost function.

Functional studies of Drosophila zinc transporters reveal the mechanism for dietary zinc absorption and regulation

PubMed Central

2013-01-01

Background Zinc is key to the function of many proteins, but the process of dietary zinc absorption is not well clarified. Current knowledge about dietary zinc absorption is fragmented, and mostly derives from incomplete mammalian studies. To gain a comprehensive picture of this process, we systematically characterized all zinc transporters (that is, the Zip and ZnT family members) for their possible roles in dietary zinc absorption in a genetically amenable model organism, Drosophila melanogaster. Results A set of plasma membrane-resident zinc transporters was identified to be responsible for absorbing zinc from the lumen into the enterocyte and the subsequent exit of zinc to the circulation. dZip1 and dZip2, two functionally overlapping zinc importers, are responsible for absorbing zinc from the lumen into the enterocyte. Exit of zinc to the circulation is mediated through another two functionally overlapping zinc exporters, dZnT1, and its homolog CG5130 (dZnT77C). Somewhat surprisingly, it appears that the array of intracellular ZnT proteins, including the Golgi-resident dZnT7, is not directly involved in dietary zinc absorption. By modulating zinc status in different parts of the body, we found that regulation of dietary zinc absorption, in contrast to that of iron, is unresponsive to bodily needs or zinc status outside the gut. The zinc transporters that are involved in dietary zinc absorption, including the importers dZip1 and dZip2, and the exporter dZnT1, are respectively regulated at the RNA and protein levels by zinc in the enterocyte. Conclusions Our study using the model organism Drosophila thus starts to reveal a comprehensive sketch of dietary zinc absorption and its regulatory control, a process that is still incompletely understood in mammalian organisms. The knowledge gained will act as a reference for future mammalian studies, and also enable an appreciation of this important process from an evolutionary perspective. PMID:24063361

Correlation between pulmonary function and brain volume in healthy elderly subjects.

PubMed

Taki, Yasuyuki; Kinomura, Shigeo; Ebihara, Satoru; Thyreau, Benjamin; Sato, Kazunori; Goto, Ryoi; Kakizaki, Masako; Tsuji, Ichiro; Kawashima, Ryuta; Fukuda, Hiroshi

2013-06-01

Cigarette smoking decreases brain regional gray matter volume and is related to chronic obstructive lung disease (COPD). COPD leads to decreased pulmonary function, which is represented by forced expiratory volume in one second percentage (FEV1.0 %); however, it is unclear if decreased pulmonary function is directly related to brain gray matter volume decline. Because there is a link between COPD and cognitive decline, revealing a direct relationship between pulmonary function and brain structure is important to better understand how pulmonary function affects brain structure and cognitive function. Therefore, the purpose of this study was to analyze whether there were significant correlations between FEV1.0 % and brain regional gray and white matter volumes using brain magnetic resonance (MR) image data from 109 community-dwelling healthy elderly individuals. Brain MR images were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. We found a significant positive correlation between the regional white matter volume of the cerebellum and FEV1.0 % after adjusting for age, sex, and intracranial volume. Our results suggest that elderly individuals who have a lower FEV1.0 % have decreased regional white matter volume in the cerebellum. Therefore, preventing decreased pulmonary function is important for cerebellar white matter volume in the healthy elderly population.

Exploration of Multi-State Conformational Dynamics and Underlying Global Functional Landscape of Maltose Binding Protein

PubMed Central

Wang, Yong; Tang, Chun; Wang, Erkang; Wang, Jin

2012-01-01

An increasing number of biological machines have been revealed to have more than two macroscopic states. Quantifying the underlying multiple-basin functional landscape is essential for understanding their functions. However, the present models seem to be insufficient to describe such multiple-state systems. To meet this challenge, we have developed a coarse grained triple-basin structure-based model with implicit ligand. Based on our model, the constructed functional landscape is sufficiently sampled by the brute-force molecular dynamics simulation. We explored maltose-binding protein (MBP) which undergoes large-scale domain motion between open, apo-closed (partially closed) and holo-closed (fully closed) states responding to ligand binding. We revealed an underlying mechanism whereby major induced fit and minor population shift pathways co-exist by quantitative flux analysis. We found that the hinge regions play an important role in the functional dynamics as well as that increases in its flexibility promote population shifts. This finding provides a theoretical explanation of the mechanistic discrepancies in PBP protein family. We also found a functional “backtracking” behavior that favors conformational change. We further explored the underlying folding landscape in response to ligand binding. Consistent with earlier experimental findings, the presence of ligand increases the cooperativity and stability of MBP. This work provides the first study to explore the folding dynamics and functional dynamics under the same theoretical framework using our triple-basin functional model. PMID:22532792

The regulatory software of cellular metabolism.

PubMed

Segrè, Daniel

2004-06-01

Understanding the regulation of metabolic pathways in the cell is like unraveling the 'software' that is running on the 'hardware' of the metabolic network. Transcriptional regulation of enzymes is an important component of this software. A recent systematic analysis of metabolic gene-expression data in Saccharomyces cerevisiae reveals a complex modular organization of co-expressed genes, which could increase our ability to understand and engineer cellular metabolic functions.

Dependency aspect of caregiver burden is uniquely related to cognitive impairment in Veterans.

PubMed

Stinson, Jennifer M; Collins, Robert L; Maestas, Kacey Little; Pacheco, Vitor; LeMaire, Ashley; Benge, Jared

2014-01-01

The psychosocial toll of caring for an individual with dementia is an important, if understudied, concept. For practitioners and researchers alike, understanding the relation between patient characteristics and different facets of caregiver burden is important for guiding treatment and prevention efforts. The current study analyzed the dimensions of caregiver burden and the relation between caregiver burden and results of neuropsychological testing. Participants included 243 dyads of caregivers and Veterans referred for neuropsychological evaluation. Caregivers completed the Zarit Burden Interview (ZBI) to assess caregiver burden. Patients completed a battery of neuropsychological tests measuring the domains of attention/processing speed, memory, language, and executive functioning. A principal components analysis of the ZBI revealed a three-factor structure: psychosocial burden, dependency burden, and guilt. Correlations with neuropsychological test performance by Veteran patients suggested that test performance in the memory, attention, processing speed, executive functioning, and emotional functioning domains were solely related to the caregiver dependency burden factor of the ZBI. Additional analyses suggested severity of dementia and number of tests in the impaired range further influenced reported caregiver burden. The current study is one of the few studies examining caregiver burden in relation to neuropsychological functioning in a mixed clinical sample and has important implications for clinical practice.

The brain network reflecting bodily self-consciousness: a functional connectivity study

PubMed Central

Ionta, Silvio; Martuzzi, Roberto; Salomon, Roy

2014-01-01

Several brain regions are important for processing self-location and first-person perspective, two important aspects of bodily self-consciousness. However, the interplay between these regions has not been clarified. In addition, while self-location and first-person perspective in healthy subjects are associated with bilateral activity in temporoparietal junction (TPJ), disturbed self-location and first-person perspective result from damage of only the right TPJ. Identifying the involved brain network and understanding the role of hemispheric specializations in encoding self-location and first-person perspective, will provide important information on system-level interactions neurally mediating bodily self-consciousness. Here, we used functional connectivity and showed that right and left TPJ are bilaterally connected to supplementary motor area, ventral premotor cortex, insula, intraparietal sulcus and occipitotemporal cortex. Furthermore, the functional connectivity between right TPJ and right insula had the highest selectivity for changes in self-location and first-person perspective. Finally, functional connectivity revealed hemispheric differences showing that self-location and first-person perspective modulated the connectivity between right TPJ, right posterior insula, and right supplementary motor area, and between left TPJ and right anterior insula. The present data extend previous evidence on healthy populations and clinical observations in neurological deficits, supporting a bilateral, but right-hemispheric dominant, network for bodily self-consciousness. PMID:24396007

An experimental analysis of granivory in a desert ecosystem: Progress report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, J.H.

1987-03-01

Controlled, replicated experiments are revealing the network of interactions that determine structure, dynamics, and energy transfer in a desert community that is functionally interconnected by the consumption of seeds (granivory). This community includes seed-eating rodents, ants, and birds, seed-producing annual and perennial plants, and other kinds of organisms that interact with these. The experiments entail removal of important species or functional groups of granivores or plants and supplementation of seed resources. The results demonstrate a large number of direct and indirect interactions that have important effects on the abundance of species and functional groups, the structure of the community, andmore » the dynamics of energy flow. The results suggest that networks of interaction are structured with sufficient overlap in resource requirements and interconnections through indirect pathways that community- and ecosystem-level processes, such as energy flow, are relatively insensitive to major perturbations in the abundance of particular species or functional groups. This preliminary finding has important implications for understanding the response of ecosystems to natural and human-caused perturbations, for the management of agricultural and other human-modified ecosystems, and for the design of perturbation-resistant networks for acquisition and distribution of human resources such energy and information. 44 refs.« less

Recent Observational Progress on Accretion Disks Around Compact Objects

NASA Astrophysics Data System (ADS)

Miller, Jon M.

2016-04-01

Studies of accretion disks around black holes and neutron stars over the last ten years have made remarkable progress. Our understanding of disk evolution as a function of mass accretion rate is pushing toward a consensus on thin/thick disk transitions; an apparent switching between disk-driven outflow modes has emerged; and monitoring observations have revealed complex spectral energy distributions wherein disk reprocessing must be important. Detailed studies of disk winds, in particular, have the potential to reveal the basic physical processes that mediate disk accretion, and to connect with numerical simulations. This talk will review these developments and look ahead to the potential of Astro-H.

ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function

PubMed Central

Collins, Natalie B.; Wilson, James B.; Bush, Thomas; Thomashevski, Andrei; Roberts, Kate J.; Jones, Nigel J.

2009-01-01

Previous work has shown several proteins defective in Fanconi anemia (FA) are phosphorylated in a functionally critical manner. FANCA is phosphorylated after DNA damage and localized to chromatin, but the site and significance of this phosphorylation are unknown. Mass spectrometry of FANCA revealed one phosphopeptide, phosphorylated on serine 1449. Serine 1449 phosphorylation was induced after DNA damage but not during S phase, in contrast to other posttranslational modifications of FA proteins. Furthermore, the S1449A mutant failed to completely correct a variety of FA-associated phenotypes. The DNA damage response is coordinated by phosphorylation events initiated by apical kinases ATM (ataxia telangectasia mutated) and ATR (ATM and Rad3-related), and ATR is essential for proper FA pathway function. Serine 1449 is in a consensus ATM/ATR site, phosphorylation in vivo is dependent on ATR, and ATR phosphorylated FANCA on serine 1449 in vitro. Phosphorylation of FANCA on serine 1449 is a DNA damage–specific event that is downstream of ATR and is functionally important in the FA pathway. PMID:19109555

Biogenesis and functions of lipid droplets in plants: Thematic Review Series: Lipid Droplet Synthesis and Metabolism: from Yeast to Man.

PubMed

Chapman, Kent D; Dyer, John M; Mullen, Robert T

2012-02-01

The compartmentation of neutral lipids in plants is mostly associated with seed tissues, where triacylglycerols (TAGs) stored within lipid droplets (LDs) serve as an essential physiological energy and carbon reserve during postgerminative growth. However, some nonseed tissues, such as leaves, flowers and fruits, also synthesize and store TAGs, yet relatively little is known about the formation or function of LDs in these tissues. Characterization of LD-associated proteins, such as oleosins, caleosins, and sterol dehydrogenases (steroleosins), has revealed surprising features of LD function in plants, including stress responses, hormone signaling pathways, and various aspects of plant growth and development. Although oleosin and caleosin proteins are specific to plants, LD-associated sterol dehydrogenases also are present in mammals, and in both plants and mammals these enzymes have been shown to be important in (steroid) hormone metabolism and signaling. In addition, several other proteins known to be important in LD biogenesis in yeasts and mammals are conserved in plants, suggesting that at least some aspects of LD biogenesis and/or function are evolutionarily conserved.

The bornavirus-derived human protein EBLN1 promotes efficient cell cycle transit, microtubule organisation and genome stability

PubMed Central

Myers, Katie N.; Barone, Giancarlo; Ganesh, Anil; Staples, Christopher J.; Howard, Anna E.; Beveridge, Ryan D.; Maslen, Sarah; Skehel, J. Mark; Collis, Spencer J.

2016-01-01

It was recently discovered that vertebrate genomes contain multiple endogenised nucleotide sequences derived from the non-retroviral RNA bornavirus. Strikingly, some of these elements have been evolutionary maintained as open reading frames in host genomes for over 40 million years, suggesting that some endogenised bornavirus-derived elements (EBL) might encode functional proteins. EBLN1 is one such element established through endogenisation of the bornavirus N gene (BDV N). Here, we functionally characterise human EBLN1 as a novel regulator of genome stability. Cells depleted of human EBLN1 accumulate DNA damage both under non-stressed conditions and following exogenously induced DNA damage. EBLN1-depleted cells also exhibit cell cycle abnormalities and defects in microtubule organisation as well as premature centrosome splitting, which we attribute in part, to improper localisation of the nuclear envelope protein TPR. Our data therefore reveal that human EBLN1 possesses important cellular functions within human cells, and suggest that other EBLs present within vertebrate genomes may also possess important cellular functions. PMID:27739501

MicroRNAs in thyroid development, function and tumorigenesis.

PubMed

Fuziwara, Cesar Seigi; Kimura, Edna Teruko

2017-11-15

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that modulate the vast majority of cellular processes. During development, the correct timing and expression of miRNAs in the tissue differentiation is essential for organogenesis and functionality. In thyroid gland, DICER and miRNAs are necessary for accurately establishing thyroid follicles and hormone synthesis. Moreover, DICER1 mutations and miRNA deregulation observed in human goiter influence thyroid tumorigenesis. The thyroid malignant transformation by MAPK oncogenes is accompanied by global miRNA changes, with a marked reduction of "tumor-suppressor" miRNAs and activation of oncogenic miRNAs. Loss of thyroid cell differentiation/function, and consequently iodine trapping impairment, is an important clinical characteristic of radioiodine-refractory thyroid cancer. However, few studies have addressed the direct role of miRNAs in thyroid gland physiology. Here, we focus on what we have learned in the thyroid follicular cell differentiation and function as revealed by cell and animal models and miRNA modulation in thyroid tumorigenesis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Lineage-specific genomics: Frequent birth and death in the human genome: The human genome contains many lineage-specific elements created by both sequence and functional turnover.

PubMed

Young, Robert S

2016-07-01

Frequent evolutionary birth and death events have created a large quantity of biologically important, lineage-specific DNA within mammalian genomes. The birth and death of DNA sequences is so frequent that the total number of these insertions and deletions in the human population remains unknown, although there are differences between these groups, e.g. transposable elements contribute predominantly to sequence insertion. Functional turnover - where the activity of a locus is specific to one lineage, but the underlying DNA remains conserved - can also drive birth and death. However, this does not appear to be a major driver of divergent transcriptional regulation. Both sequence and functional turnover have contributed to the birth and death of thousands of functional promoters in the human and mouse genomes. These findings reveal the pervasive nature of evolutionary birth and death and suggest that lineage-specific regions may play an important but previously underappreciated role in human biology and disease. © 2016 The Authors BioEssays Published by WILEY Periodicals, Inc.

Uncoupling of Protease trans-Cleavage and Helicase Activities in Pestivirus NS3

PubMed Central

Zheng, Fengwei; Lu, Guoliang; Li, Ling

2017-01-01

ABSTRACT The nonstructural protein NS3 from the Flaviviridae family is a multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and genome replication. Here we report a full-length crystal structure of the classical swine fever virus (CSFV) NS3 in complex with its NS4A protease cofactor segment (PCS) at a 2.35-Å resolution. The structure reveals a previously unidentified ∼2,200-Å2 intramolecular protease-helicase interface comprising three clusters of interactions, representing a “closed” global conformation related to the NS3-NS4A cis-cleavage event. Although this conformation is incompatible with protease trans-cleavage, it appears to be functionally important and beneficial to the helicase activity, as the mutations designed to perturb this conformation impaired both the helicase activities in vitro and virus production in vivo. Our work reveals important features of protease-helicase coordination in pestivirus NS3 and provides a key basis for how different conformational states may explicitly contribute to certain functions of this natural protease-helicase fusion protein. IMPORTANCE Many RNA viruses encode helicases to aid their RNA genome replication and transcription by unwinding structured RNA. Being naturally fused to a protease participating in viral polyprotein processing, the NS3 helicases encoded by the Flaviviridae family viruses are unique. Therefore, how these two enzyme modules coordinate in a single polypeptide is of particular interest. Here we report a previously unidentified conformation of pestivirus NS3 in complex with its NS4A protease cofactor segment (PCS). This conformational state is related to the protease cis-cleavage event and is optimal for the function of helicase. This work provides an important basis to understand how different enzymatic activities of NS3 may be achieved by the coordination between the protease and helicase through different conformational states. PMID:28835495

Revealed and stated preference valuation and transfer: A within-sample comparison of water quality improvement values

NASA Astrophysics Data System (ADS)

Ferrini, Silvia; Schaafsma, Marije; Bateman, Ian

2014-06-01

Benefit transfer (BT) methods are becoming increasingly important for environmental policy, but the empirical findings regarding transfer validity are mixed. A novel valuation survey was designed to obtain both stated preference (SP) and revealed preference (RP) data concerning river water quality values from a large sample of households. Both dichotomous choice and payment card contingent valuation (CV) and travel cost (TC) data were collected. Resulting valuations were directly compared and used for BT analyses using both unit value and function transfer approaches. WTP estimates are found to pass the convergence validity test. BT results show that the CV data produce lower transfer errors, below 20% for both unit value and function transfer, than TC data especially when using function transfer. Further, comparison of WTP estimates suggests that in all cases, differences between methods are larger than differences between study areas. Results show that when multiple studies are available, using welfare estimates from the same area but based on a different method consistently results in larger errors than transfers across space keeping the method constant.

The heptanucleotide motif GAGACGC is a key component of a cis-acting promoter element that is critical for SnSAG1 expression in Sarcocystis neurona.

PubMed

Gaji, Rajshekhar Y; Howe, Daniel K

2009-07-01

The apicomplexan parasite Sarcocystis neurona undergoes a complex process of intracellular development, during which many genes are temporally regulated. The described study was undertaken to begin identifying the basic promoter elements that control gene expression in S. neurona. Sequence analysis of the 5'-flanking region of five S. neurona genes revealed a conserved heptanucleotide motif GAGACGC that is similar to the WGAGACG motif described upstream of multiple genes in Toxoplasma gondii. The promoter region for the major surface antigen gene SnSAG1, which contains three heptanucleotide motifs within 135 bases of the transcription start site, was dissected by functional analysis using a dual luciferase reporter assay. These analyses revealed that a minimal promoter fragment containing all three motifs was sufficient to drive reporter molecule expression, with the presence and orientation of the 5'-most heptanucleotide motif being absolutely critical for promoter function. Further studies should help to identify additional sequence elements important for promoter function and for controlling gene expression during intracellular development by this apicomplexan pathogen.

Palmitoylation of proteins in cancer.

PubMed

Resh, Marilyn D

2017-04-15

Post-translational modification of proteins by attachment of palmitate serves as a mechanism to regulate protein localization and function in both normal and malignant cells. Given the essential role that palmitoylation plays in cancer cell signaling, approaches that target palmitoylated proteins and palmitoyl acyltransferases (PATs) have the potential for therapeutic intervention in cancer. Highlighted here are recent advances in understanding the importance of protein palmitoylation in tumorigenic pathways. A new study has uncovered palmitoylation sites within the epidermal growth factor receptor that regulate receptor trafficking, signaling and sensitivity to tyrosine kinase inhibitors. Global data analysis from nearly 150 cancer studies reveals genomic alterations in several PATs that may account for their ability to function as tumor suppressors or oncogenes. Selective inhibitors have recently been developed that target hedgehog acyltransferase (Hhat) and Porcupine (Porcn), the acyltransferases that modify hedgehog and Wnt proteins, respectively. These inhibitors, coupled with targeted knockdown of Hhat and Porcn, reveal the essential functions of fatty acylation of secreted morphogens in a wide variety of human tumors. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae

PubMed Central

Elefteriou, Florent; Benson, M. Douglas; Sowa, Hideaki; Starbuck, Michael; Liu, Xiuyun; Ron, David; Parada, Luis F.; Karsenty, Gerard

2009-01-01

Summary The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1ob−/− mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1ob−/− mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1ob−/− mice without affecting other organ weight, while a high-protein diet overcame Atf4−/− and Rsk2−/− mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development. PMID:17141628

Knockdown of RMI1 impairs DNA repair under DNA replication stress.

PubMed

Xu, Chang; Fang, Lianying; Kong, Yangyang; Xiao, Changyan; Yang, Mengmeng; Du, Li-Qing; Liu, Qiang

2017-12-09

RMI1 (RecQ-mediated genome instability protein 1) forms a conserved BTR complex with BLM, Topo IIIα, and RMI2, and its absence causes genome instability. It has been revealed that RMI1 localizes to nuclear foci with BLM and Topo IIIα in response to replication stress, and that RMI1 functions downstream of BLM in promoting replication elongation. However, the precise functions of RMI1 during replication stress are not completely understood. Here we report that RMI1 knockdown cells are hypersensitive to hydroxyurea (HU). Using comet assay, we show that RMI1 knockdown cells exhibit accumulation of broken DNAs after being released from HU treatment. Moreover, we demonstrate that RMI1 facilitates the recovery from activated checkpoint and resuming the cell cycle after replicative stress. Surprisingly, loss of RMI1 results in a failure of RAD51 loading onto DNA damage sites. These findings reveal the importance of RMI1 in response to replication stress, which could explain the molecular basis for its function in maintaining genome integrity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

DNA is structured as a linear "jigsaw puzzle" in the genomes of Arabidopsis, rice, and budding yeast.

PubMed

Liu, Yun-Hua; Zhang, Meiping; Wu, Chengcang; Huang, James J; Zhang, Hong-Bin

2014-01-01

Knowledge of how a genome is structured and organized from its constituent elements is crucial to understanding its biology and evolution. Here, we report the genome structuring and organization pattern as revealed by systems analysis of the sequences of three model species, Arabidopsis, rice and yeast, at the whole-genome and chromosome levels. We found that all fundamental function elements (FFE) constituting the genomes, including genes (GEN), DNA transposable elements (DTE), retrotransposable elements (RTE), simple sequence repeats (SSR), and (or) low complexity repeats (LCR), are structured in a nonrandom and correlative manner, thus leading to a hypothesis that the DNA of the species is structured as a linear "jigsaw puzzle". Furthermore, we showed that different FFE differ in their importance in the formation and evolution of the DNA jigsaw puzzle structure between species. DTE and RTE play more important roles than GEN, LCR, and SSR in Arabidopsis, whereas GEN and RTE play more important roles than LCR, SSR, and DTE in rice. The genes having multiple recognized functions play more important roles than those having single functions. These results provide useful knowledge necessary for better understanding genome biology and evolution of the species and for effective molecular breeding of rice.

Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study

PubMed Central

Rifkin-Graboi, A; Kong, L; Sim, L W; Sanmugam, S; Broekman, B F P; Chen, H; Wong, E; Kwek, K; Saw, S-M; Chong, Y-S; Gluckman, P D; Fortier, M V; Pederson, D; Meaney, M J; Qiu, A

2015-01-01

Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early-postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother–infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning. PMID:26506054

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Ronghui; Satkovich, John; Hu, Jianping

Peroxisomes are ubiquitous eukaryotic organelles that play pivotal roles in a suite of metabolic processes and often act coordinately with other organelles, such as chloroplasts and mitochondria. Peroxisomes import proteins to the peroxisome matrix by peroxins (PEX proteins), but how the function of the PEX proteins is regulated is poorly understood. In this study, we identified the Arabidopsis RING (really interesting new gene) type E3 ubiquitin ligase SP1 [suppressor of plastid protein import locus 1 (ppi1) 1] as a peroxisome membrane protein with a regulatory role in peroxisome protein import. SP1 interacts physically with the two components of the peroxisomemore » protein docking complex PEX13–PEX14 and the (RING)-finger peroxin PEX2. Loss of SP1 function suppresses defects of the pex14-2 and pex13-1 mutants, and SP1 is involved in the degradation of PEX13 and possibly PEX14 and all three RING peroxins. An in vivo ubiquitination assay showed that SP1 has the ability to promote PEX13 ubiquitination. Our study has revealed that, in addition to its previously reported function in chloroplast biogenesis, SP1 plays a role in peroxisome biogenesis. The same E3 ubiquitin ligase promotes the destabilization of components of two distinct protein-import machineries, indicating that degradation of organelle biogenesis factors by the ubiquitin–proteasome system may constitute an important regulatory mechanism in coordinating the biogenesis of metabolically linked organelles in eukaryotes.« less

Ensemble gene function prediction database reveals genes important for complex I formation in Arabidopsis thaliana.

PubMed

Hansen, Bjoern Oest; Meyer, Etienne H; Ferrari, Camilla; Vaid, Neha; Movahedi, Sara; Vandepoele, Klaas; Nikoloski, Zoran; Mutwil, Marek

2018-03-01

Recent advances in gene function prediction rely on ensemble approaches that integrate results from multiple inference methods to produce superior predictions. Yet, these developments remain largely unexplored in plants. We have explored and compared two methods to integrate 10 gene co-function networks for Arabidopsis thaliana and demonstrate how the integration of these networks produces more accurate gene function predictions for a larger fraction of genes with unknown function. These predictions were used to identify genes involved in mitochondrial complex I formation, and for five of them, we confirmed the predictions experimentally. The ensemble predictions are provided as a user-friendly online database, EnsembleNet. The methods presented here demonstrate that ensemble gene function prediction is a powerful method to boost prediction performance, whereas the EnsembleNet database provides a cutting-edge community tool to guide experimentalists. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

[The establishment, development and application of classification approach of freshwater phytoplankton based on the functional group: a review].

PubMed

Yang, Wen; Zhu, Jin-Yong; Lu, Kai-Hong; Wan, Li; Mao, Xiao-Hua

2014-06-01

Appropriate schemes for classification of freshwater phytoplankton are prerequisites and important tools for revealing phytoplanktonic succession and studying freshwater ecosystems. An alternative approach, functional group of freshwater phytoplankton, has been proposed and developed due to the deficiencies of Linnaean and molecular identification in ecological applications. The functional group of phytoplankton is a classification scheme based on autoecology. In this study, the theoretical basis and classification criterion of functional group (FG), morpho-functional group (MFG) and morphology-based functional group (MBFG) were summarized, as well as their merits and demerits. FG was considered as the optimal classification approach for the aquatic ecology research and aquatic environment evaluation. The application status of FG was introduced, with the evaluation standards and problems of two approaches to assess water quality on the basis of FG, index methods of Q and QR, being briefly discussed.

Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses.

PubMed

Kessels, Michael M; Qualmann, Britta

2015-09-01

A plethora of cell biological processes involve modulations of cellular membranes. By using extended lipid-binding interfaces, some proteins have the power to shape membranes by attaching to them. Among such membrane shapers, the superfamily of Bin-Amphiphysin-Rvs (BAR) domain proteins has recently taken center stage. Extensive structural work on BAR domains has revealed a common curved fold that can serve as an extended membrane-binding interface to modulate membrane topologies and has allowed the grouping of the BAR domain superfamily into subfamilies with structurally slightly distinct BAR domain subtypes (N-BAR, BAR, F-BAR and I-BAR). Most BAR superfamily members are expressed in the mammalian nervous system. Neurons are elaborately shaped and highly compartmentalized cells. Therefore, analyses of synapse formation and of postsynaptic reorganization processes (synaptic plasticity) - a basis for learning and memory formation - has unveiled important physiological functions of BAR domain superfamily members. These recent advances, furthermore, have revealed that the functions of BAR domain proteins include different aspects. These functions are influenced by the often complex domain organization of BAR domain proteins. In this Commentary, we review these recent insights and propose to classify BAR domain protein functions into (1) membrane shaping, (2) physical integration, (3) action through signaling components, and (4) suppression of other BAR domain functions. © 2015. Published by The Company of Biologists Ltd.

Concurrent Formation of Carbon–Carbon Bonds and Functionalized Graphene by Oxidative Carbon-Hydrogen Coupling Reaction

PubMed Central

Morioku, Kumika; Morimoto, Naoki; Takeuchi, Yasuo; Nishina, Yuta

2016-01-01

Oxidative C–H coupling reactions were conducted using graphene oxide (GO) as an oxidant. GO showed high selectivity compared with commonly used oxidants such as (diacetoxyiodo) benzene and 2,3-dichloro-5,6-dicyano-p-benzoquinone. A mechanistic study revealed that radical species contributed to the reaction. After the oxidative coupling reaction, GO was reduced to form a material that shows electron conductivity and high specific capacitance. Therefore, this system could concurrently achieve two important reactions: C–C bond formation via C–H transformation and production of functionalized graphene. PMID:27181191

Progranulin, lysosomal regulation and neurodegenerative disease.

PubMed

Kao, Aimee W; McKay, Andrew; Singh, Param Priya; Brunet, Anne; Huang, Eric J

2017-06-01

The discovery that heterozygous and homozygous mutations in the gene encoding progranulin are causally linked to frontotemporal dementia and lysosomal storage disease, respectively, reveals previously unrecognized roles of the progranulin protein in regulating lysosome biogenesis and function. Given the importance of lysosomes in cellular homeostasis, it is not surprising that progranulin deficiency has pleiotropic effects on neural circuit development and maintenance, stress response, innate immunity and ageing. This Progress article reviews recent advances in progranulin biology emphasizing its roles in lysosomal function and brain innate immunity, and outlines future avenues of investigation that may lead to new therapeutic approaches for neurodegeneration.

Super-resolution microscopy reveals structural diversity in molecular exchange among peptide amphiphile nanofibres

DOE PAGES

da Silva, Ricardo M. P.; van der Zwaag, Daan; Albertazzi, Lorenzo; ...

2016-05-19

The dynamic behaviour of supramolecular systems is an important dimension of their potential functions. Here, we report on the use of stochastic optical reconstruction microscopy to study the molecular exchange of peptide amphiphile nanofibres, supramolecular systems known to have important biomedical functions. Solutions of nanofibres labelled with different dyes (Cy3 and Cy5) were mixed, and the distribution of dyes inserting into initially single-colour nanofibres was quantified using correlative image analysis. Our observations are consistent with an exchange mechanism involving monomers or small clusters of molecules inserting randomly into a fibre. Different exchange rates are observed within the same fibre, suggestingmore » that local cohesive structures exist on the basis of beta-sheet discontinuous domains. The results reported here show that peptide amphiphile supramolecular systems can be dynamic and that their intermolecular interactions affect exchange patterns. Lastly, this information can be used to generate useful aggregate morphologies for improved biomedical function.« less

Structural bases for neurophysiological investigations of amygdaloid complex of the brain

NASA Astrophysics Data System (ADS)

Kalimullina, Liliya B.; Kalkamanov, Kh. A.; Akhmadeev, Azat V.; Zakharov, Vadim P.; Sharafullin, Ildus F.

2015-11-01

Amygdala (Am) as a part of limbic system of the brain defines such important functions as adaptive behavior of animals, formation of emotions and memory, regulation of endocrine and visceral functions. We worked out, with the help of mathematic modelling of the pattern recognition theory, principles for organization of neurophysiological and neuromorphological studies of Am nuclei, which take into account the existing heterogeneity of its formations and optimize, to a great extent, the protocol for carrying out of such investigations. The given scheme of studies of Am’s structural-functional organization at its highly-informative sections can be used as a guide for precise placement of electrodes’, cannulae’s and microsensors into particular Am nucleus in the brain with the registration not only the nucleus itself, but also its extensions. This information is also important for defining the number of slices covering specific Am nuclei which must be investigated to reveal the physiological role of a particular part of amygdaloid complex.

The phylogenetic analysis of tetraspanins projects the evolution of cell-cell interactions from unicellular to multicellular organisms.

PubMed

Huang, Shengfeng; Yuan, Shaochun; Dong, Meiling; Su, Jing; Yu, Cuiling; Shen, Yang; Xie, Xiaojin; Yu, Yanhong; Yu, Xuesong; Chen, Shangwu; Zhang, Shicui; Pontarotti, Pierre; Xu, Anlong

2005-12-01

In animals, the tetraspanins are a large superfamily of membrane proteins that play important roles in organizing various cell-cell and matrix-cell interactions and signal pathways based on such interactions. However, their origin and evolution largely remain elusive and most of the family's members are functionally unknown or less known due to difficulties of study, such as functional redundancy. In this study, we rebuilt the family's phylogeny with sequences retrieved from online databases and our cDNA library of amphioxus. We reveal that, in addition to in metazoans, various tetraspanins are extensively expressed in protozoan amoebae, fungi, and plants. We also discuss the structural evolution of tetraspanin's major extracellular domain and the relation between tetraspanin's duplication and functional redundancy. Finally, we elucidate the coevolution of tetraspanins and eukaryotes and suggest that tetraspanins play important roles in the unicell-to-multicell transition. In short, the study of tetraspanin in a phylogenetic context helps us understand the evolution of intercellular interactions.

D1 receptors physically interact with N-type calcium channels to regulate channel distribution and dendritic calcium entry.

PubMed

Kisilevsky, Alexandra E; Mulligan, Sean J; Altier, Christophe; Iftinca, Mircea C; Varela, Diego; Tai, Chao; Chen, Lina; Hameed, Shahid; Hamid, Jawed; Macvicar, Brian A; Zamponi, Gerald W

2008-05-22

Dopamine signaling through D1 receptors in the prefrontal cortex (PFC) plays a critical role in the maintenance of higher cognitive functions, such as working memory. At the cellular level, these functions are predicated to involve alterations in neuronal calcium levels. The dendrites of PFC neurons express D1 receptors and N-type calcium channels, yet little information exists regarding their coupling. Here, we show that D1 receptors potently inhibit N-type channels in dendrites of rat PFC neurons. Using coimmunoprecipitation, we demonstrate the existence of a D1 receptor-N-type channel signaling complex in this region, and we provide evidence for a direct receptor-channel interaction. Finally, we demonstrate the importance of this complex to receptor-channel colocalization in heterologous systems and in PFC neurons. Our data indicate that the N-type calcium channel is an important physiological target of D1 receptors and reveal a mechanism for D1 receptor-mediated regulation of cognitive function in the PFC.

States of curiosity modulate hippocampus-dependent learning via the dopaminergic circuit.

PubMed

Gruber, Matthias J; Gelman, Bernard D; Ranganath, Charan

2014-10-22

People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day-delayed memory tests, participants showed improved memory for information that they were curious about and for incidental material learned during states of high curiosity. Functional magnetic resonance imaging results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity-driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity to create more effective learning experiences. Copyright © 2014 Elsevier Inc. All rights reserved.

Conserved intergenic sequences revealed by CTAG-profiling in Salmonella: thermodynamic modeling for function prediction

NASA Astrophysics Data System (ADS)

Tang, Le; Zhu, Songling; Mastriani, Emilio; Fang, Xin; Zhou, Yu-Jie; Li, Yong-Guo; Johnston, Randal N.; Guo, Zheng; Liu, Gui-Rong; Liu, Shu-Lin

2017-03-01

Highly conserved short sequences help identify functional genomic regions and facilitate genomic annotation. We used Salmonella as the model to search the genome for evolutionarily conserved regions and focused on the tetranucleotide sequence CTAG for its potentially important functions. In Salmonella, CTAG is highly conserved across the lineages and large numbers of CTAG-containing short sequences fall in intergenic regions, strongly indicating their biological importance. Computer modeling demonstrated stable stem-loop structures in some of the CTAG-containing intergenic regions, and substitution of a nucleotide of the CTAG sequence would radically rearrange the free energy and disrupt the structure. The postulated degeneration of CTAG takes distinct patterns among Salmonella lineages and provides novel information about genomic divergence and evolution of these bacterial pathogens. Comparison of the vertically and horizontally transmitted genomic segments showed different CTAG distribution landscapes, with the genome amelioration process to remove CTAG taking place inward from both terminals of the horizontally acquired segment.

RNA Splicing: Regulation and Dysregulation in the Heart.

PubMed

van den Hoogenhof, Maarten M G; Pinto, Yigal M; Creemers, Esther E

2016-02-05

RNA splicing represents a post-transcriptional mechanism to generate multiple functional RNAs or proteins from a single transcript. The evolution of RNA splicing is a prime example of the Darwinian function follows form concept. A mutation that leads to a new mRNA (form) that encodes for a new functional protein (function) is likely to be retained, and this way, the genome has gradually evolved to encode for genes with multiple isoforms, thereby creating an enormously diverse transcriptome. Advances in technologies to characterize RNA populations have led to a better understanding of RNA processing in health and disease. In the heart, alternative splicing is increasingly being recognized as an important layer of post-transcriptional gene regulation. Moreover, the recent identification of several cardiac splice factors, such as RNA-binding motif protein 20 and SF3B1, not only provided important insight into the mechanisms underlying alternative splicing but also revealed how these splicing factors impact functional properties of the heart. Here, we review our current knowledge of alternative splicing in the heart, with a particular focus on the major and minor spliceosome, the factors controlling RNA splicing, and the role of alternative splicing in cardiac development and disease. © 2016 American Heart Association, Inc.

Combining functional genomics and chemical biology to identify targets of bioactive compounds.

PubMed

Ho, Cheuk Hei; Piotrowski, Jeff; Dixon, Scott J; Baryshnikova, Anastasia; Costanzo, Michael; Boone, Charles

2011-02-01

Genome sequencing projects have revealed thousands of suspected genes, challenging researchers to develop efficient large-scale functional analysis methodologies. Determining the function of a gene product generally requires a means to alter its function. Genetically tractable model organisms have been widely exploited for the isolation and characterization of activating and inactivating mutations in genes encoding proteins of interest. Chemical genetics represents a complementary approach involving the use of small molecules capable of either inactivating or activating their targets. Saccharomyces cerevisiae has been an important test bed for the development and application of chemical genomic assays aimed at identifying targets and modes of action of known and uncharacterized compounds. Here we review yeast chemical genomic assays strategies for drug target identification. Copyright © 2010 Elsevier Ltd. All rights reserved.

Allopurinol treatment and its effect on renal function in gout: a controlled study.

PubMed Central

Gibson, T; Rodgers, V; Potter, C; Simmonds, H A

1982-01-01

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys. PMID:7039523

The FUN of identifying gene function in bacterial pathogens; insights from Salmonella functional genomics.

PubMed

Hammarlöf, Disa L; Canals, Rocío; Hinton, Jay C D

2013-10-01

The availability of thousands of genome sequences of bacterial pathogens poses a particular challenge because each genome contains hundreds of genes of unknown function (FUN). How can we easily discover which FUN genes encode important virulence factors? One solution is to combine two different functional genomic approaches. First, transcriptomics identifies bacterial FUN genes that show differential expression during the process of mammalian infection. Second, global mutagenesis identifies individual FUN genes that the pathogen requires to cause disease. The intersection of these datasets can reveal a small set of candidate genes most likely to encode novel virulence attributes. We demonstrate this approach with the Salmonella infection model, and propose that a similar strategy could be used for other bacterial pathogens. Copyright © 2013 Elsevier Ltd. All rights reserved.

Quantitative functional characterization of conserved molecular interactions in the active site of mannitol 2-dehydrogenase

PubMed Central

Lucas, James E; Siegel, Justin B

2015-01-01

Enzyme active site residues are often highly conserved, indicating a significant role in function. In this study we quantitate the functional contribution for all conserved molecular interactions occurring within a Michaelis complex for mannitol 2-dehydrogenase derived from Pseudomonas fluorescens (pfMDH). Through systematic mutagenesis of active site residues, we reveal that the molecular interactions in pfMDH mediated by highly conserved residues not directly involved in reaction chemistry can be as important to catalysis as those directly involved in the reaction chemistry. This quantitative analysis of the molecular interactions within the pfMDH active site provides direct insight into the functional role of each molecular interaction, several of which were unexpected based on canonical sequence conservation and structural analyses. PMID:25752240

Structure/function relationships in serotonin transporter: new insights from the structure of a bacterial transporter.

PubMed

Rudnick, G

2006-01-01

Serotonin transporter (SERT) serves the important function of taking up serotonin (5-HT) released during serotonergic neurotransmission. It is the target for important therapeutic drugs and psychostimulants. SERT catalyzes the influx of 5-HT together with Na+ and Cl- in a 1:1:1 stoichiometry. In the same catalytic cycle, there is coupled efflux of one K+ ion. SERT is one member of a large family of amino acid and amine transporters that is believed to utilize similar mechanisms of transport. A bacterial member of this family was recently crystallized, revealing the structural basis of these transporters. In light of the new structure, previous results with SERT have been re-interpreted, providing new insight into the substrate binding site, the permeation pathway, and the conformational changes that occur during the transport cycle.

The emerging complexity of ubiquitin architecture.

PubMed

Ohtake, Fumiaki; Tsuchiya, Hikaru

2017-02-01

Ubiquitylation is an essential post-translational modification (PTM) of proteins with diverse cellular functions. Polyubiquitin chains with different topologies have different cellular roles, and are referred to as a 'ubiquitin code'. Recent studies have begun to reveal that more complex ubiquitin architectures function as important signals in several biological pathways. These include PTMs of ubiquitin itself, such as acetylated ubiquitin and phospho-ubiquitin. Moreover, important roles for heterogeneous polyubiquitin chains, such as mixed or branched chains, have been reported, which significantly increase the diversity of the ubiquitin code. In this review, we describe mass spectrometry-based methods to characterize the ubiquitin signal. We also describe recent advances in our understanding of complex ubiquitin architectures, including our own findings concerning ubiquitin acetylation and branching within polyubiquitin chains. © The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Sociodemographic Factors Differentiating the Consumer and the Motivations for Functional Food Consumption.

PubMed

Kraus, Artur; Annunziata, Azzurra; Vecchio, Riccardo

2017-02-01

The aim of this study was to determine the (1) role of gender, age, and education in the evaluation of multidimensional criteria of the purchase of functional products, which were (a) quality and organoleptic attributes, (b) attributes of packaging and labeling, (c) healthful properties, (d) functional components, (e) base product (carrier) and (2) most important motives for the purchase and consumption of functional food among consumers of different sociodemographic profiles. The data were collected in direct interviews. The sample (n = 200) consisted of 137 women and 63 men age 18-60 years. The research tool was a questionnaire divided into 4 sections. The first one included quality attributes. The second one included healthful properties, functional components, and carriers. The third one concerned the motives for purchasing functional food and included the consequences and values. In the fourth section the participants were asked about gender, age, and education. Gender, age, and education differentiated the criteria influencing the decision to purchase functional food. Women, older people (35-60 years), and those with university education attach the greatest importance to naturalness, nutritional value, freshness, food safety, and quality guarantee. Clear differences between men and women appear in the field of functional components, which are significantly more important for women than for men. Gender, age, and education essentially differentiate the preferences for base product (carrier). Young men prefer meat products in the role of functional carriers. In turn, women and older men prefer cereal products as basic functional carriers. Young consumers are more open to high-technology food processing. Motivations are differentiated by age and gender. Young men, as opposed to women and older men, attach less importance to functional and psychological consequences: improvement of health, healthy eating, conscious choice, and health promotion. Women and older men are more interested in health safety and are more responsible for their health. Among young men, lower self-esteem can be found. The analysis conducted revealed that groups of consumers are significantly different from each other in the evaluation of the significance of each of the variables in the selection of functional food. Sociodemographic factors differentiate the motivations for consumption of functional food.

Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication.

PubMed

Ren, Xiaodi; Siegel, Rachael; Kim, Unkyu; Roeder, Robert G

2011-05-06

B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in Igh promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated Igh promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3' enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3' enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. Copyright © 2011 Elsevier Inc. All rights reserved.

Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication

PubMed Central

Ren, Xiaodi; Siegel, Rachael; Kim, Unkyu; Roeder, Robert G.

2011-01-01

Summary B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in IgH promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated IgH promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3′enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3′enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. PMID:21549311

Analysis of nucleotide diversity among alleles of the major bacterial blight resistance gene Xa27 in cultivars of rice (Oryza sativa) and its wild relatives.

PubMed

Bimolata, Waikhom; Kumar, Anirudh; Sundaram, Raman Meenakshi; Laha, Gouri Shankar; Qureshi, Insaf Ahmed; Reddy, Gajjala Ashok; Ghazi, Irfan Ahmad

2013-08-01

Xa27 is one of the important R-genes, effective against bacterial blight disease of rice caused by Xanthomonas oryzae pv. oryzae (Xoo). Using natural population of Oryza, we analyzed the sequence variation in the functionally important domains of Xa27 across the Oryza species. DNA sequences of Xa27 alleles from 27 rice accessions revealed higher nucleotide diversity among the reported R-genes of rice. Sequence polymorphism analysis revealed synonymous and non-synonymous mutations in addition to a number of InDels in non-coding regions of the gene. High sequence variation was observed in the promoter region including the 5'UTR with 'π' value 0.00916 and 'θ w ' = 0.01785. Comparative analysis of the identified Xa27 alleles with that of IRBB27 and IR24 indicated the operation of both positive selection (Ka/Ks > 1) and neutral selection (Ka/Ks ≈ 0). The genetic distances of alleles of the gene from Oryza nivara were nearer to IRBB27 as compared to IR24. We also found the presence of conserved and null UPT (upregulated by transcriptional activator) box in the isolated alleles. Considerable amino acid polymorphism was localized in the trans-membrane domain for which the functional significance is yet to be elucidated. However, the absence of functional UPT box in all the alleles except IRBB27 suggests the maintenance of single resistant allele throughout the natural population.

Deep Surveying of the Transcriptional and Alternative Splicing Signatures for Decidual CD8+ T Cells at the First Trimester of Human Healthy Pregnancy.

PubMed

Zeng, Weihong; Liu, Xinmei; Liu, Zhicui; Zheng, Ying; Yu, Tiantian; Fu, Shaliu; Li, Xiao; Zhang, Jing; Zhang, Siming; Ma, Xiaoling; Liu, Xiao-Rui; Qin, Xiaoli; Khanniche, Asma; Zhang, Yan; Tian, Fuju; Lin, Yi

2018-01-01

Decidual CD8 + (dCD8) T cells have been proposed to play important roles in immune protection against the invading pathogens and in tolerance toward the growing semi-allogeneic fetus during early pregnancy. However, their phenotypic and functional characteristics remain poorly defined. Here, we performed the first analysis of the transcriptional and alternative splicing (AS) signatures for human first-trimester dCD8 T cells using high-throughput mRNA sequencing. Our data revealed that dCD8 T cells have distinct transcriptional and AS landscapes when compared with their autologous peripheral blood CD8 + (pCD8) T counterparts. Furthermore, human dCD8 T cells were observed to contain CD8-Treg and effector-memory T-cell subsets, and display enhanced functionality in terms of degranulation and cytokine production on a per-cell basis. Additionally, we have identified the novel splice junctions that use a high ratio of the non-canonical splicing motif GC-AG and found that AS is not a major contributor to the gene expression-level changes between paired pCD8 and dCD8 T cells. Together, our findings not only provide a comprehensive framework of the transcriptional and AS landscapes but also reveal the functional feature of human dCD8 T cells, which are of great importance in understanding the biology of these cells and the physiology of human healthy pregnancy.

The implication of salience network abnormalities in young male adult smokers.

PubMed

Li, Yangding; Yuan, Kai; Guan, Yanyan; Cheng, Jiadong; Bi, Yanzhi; Shi, Sha; Xue, Ting; Lu, Xiaoqi; Qin, Wei; Yu, Dahua; Tian, Jie

2017-08-01

Studying the neural correlates of smoking behaviors in young adulthood is of great importance to improve treatment outcomes. In previous addiction studies, the important roles of the salience network (SN) in drug cue processing and cognitive control have been revealed. Unfortunately, few studies focused on the resting-state functional connectivity and structural integrity abnormalities of SN in young adult smokers, and less is known about its association with smoking behaviors and cognitive control deficits. Thirty-one young male adult smokers and 30 age-, education- and gender-matched nonsmokers participated in this study. The structural and functional connectivity differences of SN were investigated between young adult smokers and nonsmokers by using diffusion tensor imaging (DTI) and resting-state functional connectivity (RSFC), which were then correlated with the smoking behavioral assessments (pack-years and Fagerström Test for Nicotine Dependence (FTND)) as well as impaired cognitive control measured by the Stroop task. Within SN, reduced RSFC and increased fractional anisotropy (FA) were found between the anterior cingulate cortex (ACC) and the right insula in young adult smokers relative to nonsmokers. The RSFC between the ACC and right insula was negatively correlated with the number of errors during the incongruent condition of the Stroop task in young adult smokers. Additionally, the right insula-ACC RSFC was negatively correlated with pack-years in young adult smokers. Our results revealed abnormal RSFC and structural integrity within the SN in young adult smokers, which shed new insights into the neural mechanism of nicotine dependence.

Substituted cysteine accessibility method (SCAM) analysis of the transport domain of human concentrative nucleoside transporter 3 (hCNT3) and other family members reveals features of structural and functional importance

PubMed Central

Mulinta, Ras; Yao, Sylvia Y. M.; Ng, Amy M. L.; Cass, Carol E.; Young, James D.

2017-01-01

The human SLC28 family of concentrative nucleoside transporter (CNT) proteins has three members: hCNT1, hCNT2, and hCNT3. Na+-coupled hCNT1 and hCNT2 transport pyrimidine and purine nucleosides, respectively, whereas hCNT3 transports both pyrimidine and purine nucleosides utilizing Na+ and/or H+ electrochemical gradients. Escherichia coli CNT family member NupC resembles hCNT1 in permeant selectivity but is H+-coupled. Using heterologous expression in Xenopus oocytes and the engineered cysteine-less hCNT3 protein hCNT3(C−), substituted cysteine accessibility method analysis with the membrane-impermeant thiol reactive reagent p-chloromercuribenzene sulfonate was performed on the transport domain (interfacial helix 2, hairpin 1, putative transmembrane domain (TM) 7, and TM8), as well as TM9 of the scaffold domain of the protein. This systematic scan of the entire C-terminal half of hCNT3(C−) together with parallel studies of the transport domain of wild-type hCNT1 and the corresponding TMs of cysteine-less NupC(C−) yielded results that validate the newly developed structural homology model of CNT membrane architecture for human CNTs, revealed extended conformationally mobile regions within transport-domain TMs, identified pore-lining residues of functional importance, and provided evidence of an emerging novel elevator-type mechanism of transporter function. PMID:28385889

Increased Range of Motion Is Important for Functional Outcome and Satisfaction After Total Knee Arthroplasty in Asian Patients.

PubMed

Ha, Chul-Won; Park, Yong-Beom; Song, Young-Suk; Kim, Jun-Ho; Park, Yong-Geun

2016-06-01

Although range of motion (ROM) is considered as an important factor for good outcome after total knee arthroplasty (TKA), the association of the degree of ROM with functional outcome and patient satisfaction is debated. We, therefore, investigated whether increased ROM would affect functional outcome and patient satisfaction after TKA in Asian patients. We reviewed 630 patients who underwent primary TKA with minimum 2-year follow-up. Clinical outcomes were evaluated by Knee Society (KS) score, Western Ontario and McMaster Universities osteoarthritis index, and high-flexion knee score. Patient satisfaction was evaluated using a validated questionnaire. The association of ROM and change in ROM (cROM) with clinical outcomes and satisfaction were analyzed using partial correlation analysis and multiple median regression analysis. All functional scores showed significant correlation with postoperative ROM (r = 0.129, P = .001 in Knee Society score; r = -0.101, P = .012 in Western Ontario and McMaster Universities osteoarthritis index; r = 0.183, P < .001 in high-flexion knee score). cROM correlated with satisfaction (r = 0.192, P = .005). Postoperative ROM and cROM were revealed as predisposing factors affecting function outcome using multivariable regression analysis. cROM was found as a predisposing factor affecting satisfaction. Based on the results of this study, ROM positively associated with functional outcome and cROM positively associated with patient satisfaction after TKA. These findings suggest that increased ROM after TKA is an important factor for functional outcome and satisfaction in Asian patients. Copyright © 2015 Elsevier Inc. All rights reserved.

The natural cytotoxicity in cosmonauts on board space stations

NASA Astrophysics Data System (ADS)

Meshkov, D.; Rykova, M.

The nature of the changes of resistance to infection seems to be very important. Our studies indicate that different functions of natural killers could be depressed after the spaceflight. The decrease of the percentage of the lymphocytes that can bind target cells lead to the lowering of the "active" NK level and this can be resulted in the depression of total NK activity and lowering of resistance to viral and tumor antigens. The investigation of natural killer cells in cosmonauts before and after short and long-term spaceflights also revealed the important role of spaceflight duration, stress and individual immune reactivity.

Lipid Droplet-Associated Proteins (LDAPs) Are Required for the Dynamic Regulation of Neutral Lipid Compartmentation in Plant Cells1

PubMed Central

Park, Sunjung; Wu, Peng

2016-01-01

Eukaryotic cells compartmentalize neutral lipids into organelles called lipid droplets (LDs), and while much is known about the role of LDs in storing triacylglycerols in seeds, their biogenesis and function in nonseed tissues are poorly understood. Recently, we identified a class of plant-specific, lipid droplet-associated proteins (LDAPs) that are abundant components of LDs in nonseed cell types. Here, we characterized the three LDAPs in Arabidopsis (Arabidopsis thaliana) to gain insight to their targeting, assembly, and influence on LD function and dynamics. While all three LDAPs targeted specifically to the LD surface, truncation analysis of LDAP3 revealed that essentially the entire protein was required for LD localization. The association of LDAP3 with LDs was detergent sensitive, but the protein bound with similar affinity to synthetic liposomes of various phospholipid compositions, suggesting that other factors contributed to targeting specificity. Investigation of LD dynamics in leaves revealed that LD abundance was modulated during the diurnal cycle, and characterization of LDAP misexpression mutants indicated that all three LDAPs were important for this process. LD abundance was increased significantly during abiotic stress, and characterization of mutant lines revealed that LDAP1 and LDAP3 were required for the proper induction of LDs during heat and cold temperature stress, respectively. Furthermore, LDAP1 was required for proper neutral lipid compartmentalization and triacylglycerol degradation during postgerminative growth. Taken together, these studies reveal that LDAPs are required for the maintenance and regulation of LDs in plant cells and perform nonredundant functions in various physiological contexts, including stress response and postgerminative growth. PMID:26896396

Metagenomic analysis of microbial consortia enriched from compost: new insights into the role of Actinobacteria in lignocellulose decomposition.

PubMed

Wang, Cheng; Dong, Da; Wang, Haoshu; Müller, Karin; Qin, Yong; Wang, Hailong; Wu, Weixiang

2016-01-01

Compost habitats sustain a vast ensemble of microbes specializing in the degradation of lignocellulosic plant materials and are thus important both for their roles in the global carbon cycle and as potential sources of biochemical catalysts for advanced biofuels production. Studies have revealed substantial diversity in compost microbiomes, yet how this diversity relates to functions and even to the genes encoding lignocellulolytic enzymes remains obscure. Here, we used a metagenomic analysis of the rice straw-adapted (RSA) microbial consortia enriched from compost ecosystems to decipher the systematic and functional contexts within such a distinctive microbiome. Analyses of the 16S pyrotag library and 5 Gbp of metagenomic sequence showed that the phylum Actinobacteria was the predominant group among the Bacteria in the RSA consortia, followed by Proteobacteria, Firmicutes, Chloroflexi, and Bacteroidetes. The CAZymes profile revealed that CAZyme genes in the RSA consortia were also widely distributed within these bacterial phyla. Strikingly, about 46.1 % of CAZyme genes were from actinomycetal communities, which harbored a substantially expanded catalog of the cellobiohydrolase, β-glucosidase, acetyl xylan esterase, arabinofuranosidase, pectin lyase, and ligninase genes. Among these communities, a variety of previously unrecognized species was found, which reveals a greater ecological functional diversity of thermophilic Actinobacteria than previously assumed. These data underline the pivotal role of thermophilic Actinobacteria in lignocellulose biodegradation processes in the compost habitat. Besides revealing a new benchmark for microbial enzymatic deconstruction of lignocelluloses, the results suggest that actinomycetes found in compost ecosystems are potential candidates for mining efficient lignocellulosic enzymes in the biofuel industry.

A Graph Approach to Mining Biological Patterns in the Binding Interfaces.

PubMed

Cheng, Wen; Yan, Changhui

2017-01-01

Protein-RNA interactions play important roles in the biological systems. Searching for regular patterns in the Protein-RNA binding interfaces is important for understanding how protein and RNA recognize each other and bind to form a complex. Herein, we present a graph-mining method for discovering biological patterns in the protein-RNA interfaces. We represented known protein-RNA interfaces using graphs and then discovered graph patterns enriched in the interfaces. Comparison of the discovered graph patterns with UniProt annotations showed that the graph patterns had a significant overlap with residue sites that had been proven crucial for the RNA binding by experimental methods. Using 200 patterns as input features, a support vector machine method was able to classify protein surface patches into RNA-binding sites and non-RNA-binding sites with 84.0% accuracy and 88.9% precision. We built a simple scoring function that calculated the total number of the graph patterns that occurred in a protein-RNA interface. That scoring function was able to discriminate near-native protein-RNA complexes from docking decoys with a performance comparable with that of a state-of-the-art complex scoring function. Our work also revealed possible patterns that might be important for binding affinity.

Vitamin supplementation by gut symbionts ensures metabolic homeostasis in an insect host

PubMed Central

Salem, Hassan; Bauer, Eugen; Strauss, Anja S.; Vogel, Heiko; Marz, Manja; Kaltenpoth, Martin

2014-01-01

Despite the demonstrated functional importance of gut microbes, our understanding of how animals regulate their metabolism in response to nutritionally beneficial symbionts remains limited. Here, we elucidate the functional importance of the African cotton stainer's (Dysdercus fasciatus) association with two actinobacterial gut symbionts and subsequently examine the insect's transcriptional response following symbiont elimination. In line with bioassays demonstrating the symbionts' contribution towards host fitness through the supplementation of B vitamins, comparative transcriptomic analyses of genes involved in import and processing of B vitamins revealed an upregulation of gene expression in aposymbiotic (symbiont-free) compared with symbiotic individuals; an expression pattern that is indicative of B vitamin deficiency in animals. Normal expression levels of these genes, however, can be restored by either artificial supplementation of B vitamins into the insect's diet or reinfection with the actinobacterial symbionts. Furthermore, the functional characterization of the differentially expressed thiamine transporter 2 through heterologous expression in Xenopus laevis oocytes confirms its role in cellular uptake of vitamin B1. These findings demonstrate that despite an extracellular localization, beneficial gut microbes can be integral to the host's metabolic homeostasis, reminiscent of bacteriome-localized intracellular mutualists. PMID:25339726

Genome sequencing and comparative genomics reveal a repertoire of putative pathogenicity genes in chilli anthracnose fungus Colletotrichum truncatum.

PubMed

Rao, Soumya; Nandineni, Madhusudan R

2017-01-01

Colletotrichum truncatum, a major fungal phytopathogen, causes the anthracnose disease on an economically important spice crop chilli (Capsicum annuum), resulting in huge economic losses in tropical and sub-tropical countries. It follows a subcuticular intramural infection strategy on chilli with a short, asymptomatic, endophytic phase, which contrasts with the intracellular hemibiotrophic lifestyle adopted by most of the Colletotrichum species. However, little is known about the molecular determinants and the mechanism of pathogenicity in this fungus. A high quality whole genome sequence and gene annotation based on transcriptome data of an Indian isolate of C. truncatum from chilli has been obtained. Analysis of the genome sequence revealed a rich repertoire of pathogenicity genes in C. truncatum encoding secreted proteins, effectors, plant cell wall degrading enzymes, secondary metabolism associated proteins, with potential roles in the host-specific infection strategy, placing it next only to the Fusarium species. The size of genome assembly, number of predicted genes and some of the functional categories were similar to other sequenced Colletotrichum species. The comparative genomic analyses with other species and related fungi identified some unique genes and certain highly expanded gene families of CAZymes, proteases and secondary metabolism associated genes in the genome of C. truncatum. The draft genome assembly and functional annotation of potential pathogenicity genes of C. truncatum provide an important genomic resource for understanding the biology and lifestyle of this important phytopathogen and will pave the way for designing efficient disease control regimens.

N-Myc Interactor Inhibits Prototype Foamy Virus by Sequestering Viral Tas Protein in the Cytoplasm

PubMed Central

Hu, Xiaomei; Yang, Wei; Liu, Ruikang; Geng, Yunqi; Qiao, Wentao

2014-01-01

ABSTRACT Foamy viruses (FVs) are complex retroviruses that establish lifelong persistent infection without evident pathology. However, the roles of cellular factors in FV latency are poorly understood. This study revealed that N-Myc interactor (Nmi) could inhibit the replication of prototype foamy virus (PFV). Overexpression of Nmi reduced PFV replication, whereas its depletion by small interfering RNA increased PFV replication. The Nmi-mediated impairment of PFV replication resulted from the diminished transactivation by PFV Tas of the viral long terminal repeat (LTR) and an internal promoter (IP). Nmi was determined to interact with Tas and abrogate its function by sequestration in the cytoplasm. In addition, human and bovine Nmi proteins were found to inhibit the replication of bovine foamy virus (BFV) and PFV. Together, these results indicate that Nmi inhibits both human and bovine FVs by interfering with the transactivation function of Tas and may have a role in the host defense against FV infection. IMPORTANCE From this study, we report that the N-Myc interactor (Nmi), an interferon-induced protein, can interact with the regulatory protein Tas of the prototype foamy virus and sequester it in the cytoplasm. The results of this study suggest that Nmi plays an important role in maintaining foamy virus latency and may reveal a new pathway in the interferon-mediated antiviral barrier against viruses. These findings are important for understanding virus-host relationships not only with FVs but potentially for other retroviruses as well. PMID:24719420

Genome sequencing and comparative genomics reveal a repertoire of putative pathogenicity genes in chilli anthracnose fungus Colletotrichum truncatum

PubMed Central

Rao, Soumya

2017-01-01

Colletotrichum truncatum, a major fungal phytopathogen, causes the anthracnose disease on an economically important spice crop chilli (Capsicum annuum), resulting in huge economic losses in tropical and sub-tropical countries. It follows a subcuticular intramural infection strategy on chilli with a short, asymptomatic, endophytic phase, which contrasts with the intracellular hemibiotrophic lifestyle adopted by most of the Colletotrichum species. However, little is known about the molecular determinants and the mechanism of pathogenicity in this fungus. A high quality whole genome sequence and gene annotation based on transcriptome data of an Indian isolate of C. truncatum from chilli has been obtained. Analysis of the genome sequence revealed a rich repertoire of pathogenicity genes in C. truncatum encoding secreted proteins, effectors, plant cell wall degrading enzymes, secondary metabolism associated proteins, with potential roles in the host-specific infection strategy, placing it next only to the Fusarium species. The size of genome assembly, number of predicted genes and some of the functional categories were similar to other sequenced Colletotrichum species. The comparative genomic analyses with other species and related fungi identified some unique genes and certain highly expanded gene families of CAZymes, proteases and secondary metabolism associated genes in the genome of C. truncatum. The draft genome assembly and functional annotation of potential pathogenicity genes of C. truncatum provide an important genomic resource for understanding the biology and lifestyle of this important phytopathogen and will pave the way for designing efficient disease control regimens. PMID:28846714

Immune Selection In Vitro Reveals Human Immunodeficiency Virus Type 1 Nef Sequence Motifs Important for Its Immune Evasion Function In Vivo

PubMed Central

Lee, Patricia; Ng, Hwee L.; Yang, Otto O.

2012-01-01

Human immunodeficiency virus type 1 (HIV-1) Nef downregulates major histocompatibility complex class I (MHC-I), impairing the clearance of infected cells by CD8+ cytotoxic T lymphocytes (CTLs). While sequence motifs mediating this function have been determined by in vitro mutagenesis studies of laboratory-adapted HIV-1 molecular clones, it is unclear whether the highly variable Nef sequences of primary isolates in vivo rely on the same sequence motifs. To address this issue, nef quasispecies from nine chronically HIV-1-infected persons were examined for sequence evolution and altered MHC-I downregulatory function under Gag-specific CTL immune pressure in vitro. This selection resulted in decreased nef diversity and strong purifying selection. Site-by-site analysis identified 13 codons undergoing purifying selection and 1 undergoing positive selection. Of the former, only 6 have been reported to have roles in Nef function, including 4 associated with MHC-I downregulation. Functional testing of naturally occurring in vivo polymorphisms at the 7 sites with no previously known functional role revealed 3 mutations (A84D, Y135F, and G140R) that ablated MHC-I downregulation and 3 (N52A, S169I, and V180E) that partially impaired MHC-I downregulation. Globally, the CTL pressure in vitro selected functional Nef from the in vivo quasispecies mixtures that predominately lacked MHC-I downregulatory function at the baseline. Overall, these data demonstrate that CTL pressure exerts a strong purifying selective pressure for MHC-I downregulation and identifies novel functional motifs present in Nef sequences in vivo. PMID:22553319

Temperature regulates methane production through the function centralization of microbial community in anaerobic digestion.

PubMed

Lin, Qiang; De Vrieze, Jo; He, Guihua; Li, Xiangzhen; Li, Jiabao

2016-09-01

Temperature is crucial for the performance of anaerobic digestion process. In this study of anaerobic digestion of swine manure, the relationship between the microbial gene expression and methane production at different temperatures (25-55°C) was revealed through metatranscriptomic analysis. Daily methane production and total biogas production increased with temperature up to 50°C, but decreased at 55°C. The functional gene expression showed great variation at different temperatures. The function centralization (opposite to alpha-diversity), assessed by the least proportions of functional pathways contributing for at least 50% of total reads positively correlated to methane production. Temperature regulated methane production probably through reducing the diversity of functional pathways, but enhancing central functional pathways, so that most of cellular activities and resource were invested in methanogenesis and related pathways, enhancing the efficiency of conversion of substrates to methane. This research demonstrated the importance of function centralization for efficient system functioning. Copyright © 2016 Elsevier Ltd. All rights reserved.

Environmental drivers of heterogeneity in the trophic-functional structure of protozoan communities during an annual cycle in a coastal ecosystem.

PubMed

Xu, Guangjian; Yang, Eun Jin; Xu, Henglong

2017-08-15

Trophic-functional groupings are an important biological trait to summarize community structure in functional space. The heterogeneity of the tropic-functional pattern of protozoan communities and its environmental drivers were studied in coastal waters of the Yellow Sea during a 1-year cycle. Samples were collected using the glass slide method at four stations within a water pollution gradient. A second-stage matrix-based analysis was used to summarize spatial variation in the annual pattern of the functional structure. A clustering analysis revealed significant variability in the trophic-functional pattern among the four stations during the 1-year cycle. The heterogeneity in the trophic-functional pattern of the communities was significantly related to changes in environmental variables, particularly ammonium-nitrogen and nitrates, alone or in combination with dissolved oxygen. These results suggest that the heterogeneity in annual patterns of protozoan trophic-functional structure may reflect water quality status in coastal ecosystems. Copyright © 2017. Published by Elsevier Ltd.

Bacterial endophyte communities of three agricultural important grass species differ in their response towards management regimes

NASA Astrophysics Data System (ADS)

Wemheuer, Franziska; Kaiser, Kristin; Karlovsky, Petr; Daniel, Rolf; Vidal, Stefan; Wemheuer, Bernd

2017-01-01

Endophytic bacteria are critical for plant growth and health. However, compositional and functional responses of bacterial endophyte communities towards agricultural practices are still poorly understood. Hence, we analyzed the influence of fertilizer application and mowing frequency on bacterial endophytes in three agriculturally important grass species. For this purpose, we examined bacterial endophytic communities in aerial plant parts of Dactylis glomerata L., Festuca rubra L., and Lolium perenne L. by pyrotag sequencing of bacterial 16S rRNA genes over two consecutive years. Although management regimes influenced endophyte communities, observed responses were grass species-specific. This might be attributed to several bacteria specifically associated with a single grass species. We further predicted functional profiles from obtained 16S rRNA data. These profiles revealed that predicted abundances of genes involved in plant growth promotion or nitrogen metabolism differed between grass species and between management regimes. Moreover, structural and functional community patterns showed no correlation to each other indicating that plant species-specific selection of endophytes is driven by functional rather than phylogenetic traits. The unique combination of 16S rRNA data and functional profiles provided a holistic picture of compositional and functional responses of bacterial endophytes in agricultural relevant grass species towards management practices.

The Biogeographic Pattern of Microbial Functional Genes along an Altitudinal Gradient of the Tibetan Pasture

PubMed Central

Qi, Qi; Zhao, Mengxin; Wang, Shiping; Ma, Xingyu; Wang, Yuxuan; Gao, Ying; Lin, Qiaoyan; Li, Xiangzhen; Gu, Baohua; Li, Guoxue; Zhou, Jizhong; Yang, Yunfeng

2017-01-01

As the highest place of the world, the Tibetan plateau is a fragile ecosystem. Given the importance of microbial communities in driving soil nutrient cycling, it is of interest to document the microbial biogeographic pattern here. We adopted a microarray-based tool named GeoChip 4.0 to investigate grassland microbial functional genes along an elevation gradient from 3200 to 3800 m above sea level open to free grazing by local herdsmen and wild animals. Interestingly, microbial functional diversities increase with elevation, so does the relative abundances of genes associated with carbon degradation, nitrogen cycling, methane production, cold shock and oxygen limitation. The range of Shannon diversities (10.27–10.58) showed considerably smaller variation than what was previously observed at ungrazed sites nearby (9.95–10.65), suggesting the important role of livestock grazing on microbial diversities. Closer examination showed that the dissimilarity of microbial community at our study sites increased with elevations, revealing an elevation-decay relationship of microbial functional genes. Both microbial functional diversity and the number of unique genes increased with elevations. Furthermore, we detected a tight linkage of greenhouse gas (CO2) and relative abundances of carbon cycling genes. Our biogeographic study provides insights on microbial functional diversity and soil biogeochemical cycling in Tibetan pastures. PMID:28659870

The algebraic criteria for the stability of control systems

NASA Technical Reports Server (NTRS)

Cremer, H.; Effertz, F. H.

1986-01-01

This paper critically examines the standard algebraic criteria for the stability of linear control systems and their proofs, reveals important previously unnoticed connections, and presents new representations. Algebraic stability criteria have also acquired significance for stability studies of non-linear differential equation systems by the Krylov-Bogoljubov-Magnus Method, and allow realization conditions to be determined for classes of broken rational functions as frequency characteristics of electrical network.

Chromatin replication: TRANSmitting the histone code

PubMed Central

Chang, Han-Wen; Studitsky, Vasily M.

2017-01-01

Efficient overcoming of the nucleosomal barrier and accurate maintenance of associated histone marks during chromatin replication are essential for normal functioning of the cell. Recent studies revealed new protein factors and histone modifications contributing to overcoming the nucleosomal barrier, and suggested an important role for DNA looping in survival of the original histones during replication. These studies suggest new possible mechanisms for transmitting the histone code to next generations of cells. PMID:28393112

Gladiolus hybridus ABSCISIC ACID INSENSITIVE 5 (GhABI5) is an important transcription factor in ABA signaling that can enhance Gladiolus corm dormancy and Arabidopsis seed dormancy.

PubMed

Wu, Jian; Seng, Shanshan; Sui, Juanjuan; Vonapartis, Eliana; Luo, Xian; Gong, Benhe; Liu, Chen; Wu, Chenyu; Liu, Chao; Zhang, Fengqin; He, Junna; Yi, Mingfang

2015-01-01

The phytohormone abscisic acid (ABA) regulates plant development and is crucial for abiotic stress response. In this study, cold storage contributes to reducing endogenous ABA content, resulting in dormancy breaking of Gladiolus. The ABA inhibitor fluridone also promotes germination, suggesting that ABA is an important hormone that regulates corm dormancy. Here, we report the identification and functional characterization of the Gladiolus ABI5 homolog (GhABI5), which is a basic leucine zipper motif transcriptional factor (TF). GhABI5 is expressed in dormant vegetative organs (corm, cormel, and stolon) as well as in reproductive organs (stamen), and it is up-regulated by ABA or drought. Complementation analysis reveals that GhABI5 rescues the ABA insensitivity of abi5-3 during seed germination and induces the expression of downstream ABA response genes in Arabidopsis thaliana (EM1, EM6, and RD29B). Down-regulation of GhABI5 in dormant cormels via virus induced gene silence promotes sprouting and reduces the expression of downstream genes (GhLEA and GhRD29B). The results of this study reveal that GhABI5 regulates bud dormancy (vegetative organ) in Gladiolus in addition to its well-studied function in Arabidopsis seeds (reproductive organ).

mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation

PubMed Central

Matthews, Mary P.; Martin, Sally K.; Xie, Jianling; Ooi, Soo Siang; Walkley, Carl R.; Codrington, John D.; Ruegg, Markus A.; Hall, Michael N.; Proud, Christopher G.; Gronthos, Stan; Zannettino, Andrew C. W.

2017-01-01

ABSTRACT The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be determined. To investigate this question, we disrupted mTORC1 function in preosteoblasts by targeted deletion of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion caused a marked reduction in pre- and postnatal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, as well as the associated increase in skeletal fragility, was due to a reduction in osteoblast function. In vitro, osteoblasts derived from knockout mice display a reduced osteogenic potential, and an assessment of bone-developmental markers in Rptor knockout osteoblasts revealed a transcriptional profile consistent with an immature osteoblast phenotype suggesting that osteoblast differentiation was stalled early in osteogenesis. Metabolic labeling and an assessment of cell size of Rptor knockout osteoblasts revealed a significant decrease in protein synthesis, a major driver of cell growth. These findings demonstrate that mTORC1 plays an important role in skeletal development by regulating mRNA translation during preosteoblast differentiation. PMID:28069737

Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice.

PubMed

Jones, Leslie C; McCarthy, Kristin A; Beard, John L; Keen, Carl L; Jones, Byron C

2006-01-01

Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.

Mid-Task Break Improves Global Integration of Functional Connectivity in Lower Alpha Band

PubMed Central

Li, Junhua; Lim, Julian; Chen, Yu; Wong, Kianfoong; Thakor, Nitish; Bezerianos, Anastasios; Sun, Yu

2016-01-01

Numerous efforts have been devoted to revealing neurophysiological mechanisms of mental fatigue, aiming to find an effective way to reduce the undesirable fatigue-related outcomes. Until recently, mental fatigue is thought to be related to functional dysconnectivity among brain regions. However, the topological representation of brain functional connectivity altered by mental fatigue is only beginning to be revealed. In the current study, we applied a graph theoretical approach to analyse such topological alterations in the lower alpha band (8~10 Hz) of EEG data from 20 subjects undergoing a two-session experiment, in which one session includes four successive blocks with visual oddball tasks (session 1) whereas a mid-task break was introduced in the middle of four task blocks in the other session (session 2). Phase lag index (PLI) was then employed to measure functional connectivity strengths for all pairs of EEG channels. Behavior and connectivity maps were compared between the first and last task blocks in both sessions. Inverse efficiency scores (IES = reaction time/response accuracy) were significantly increased in the last task block, showing a clear effect of time-on-task in participants. Furthermore, a significant block-by-session interaction was revealed in the IES, suggesting the effectiveness of the mid-task break on maintaining task performance. More importantly, a significant session-independent deficit of global integration and an increase of local segregation were found in the last task block across both sessions, providing further support for the presence of a reshaped topology in functional brain connectivity networks under fatigue state. Moreover, a significant block-by-session interaction was revealed in the characteristic path length, small-worldness, and global efficiency, attributing to the significantly disrupted network topology in session 1 in comparison of the maintained network structure in session 2. Specifically, we found increased nodal betweenness centrality in several channels resided in frontal regions in session 1, resembling the observations of more segregated global architecture under fatigue state. Taken together, our findings provide insights into the substrates of brain functional dysconnectivity patterns for mental fatigue and reiterate the effectiveness of the mid-task break on maintaining brain network efficiency. PMID:27378894

Functional mapping of language networks in the normal brain using a word-association task.

PubMed

Ghosh, Shantanu; Basu, Amrita; Kumaran, Senthil S; Khushu, Subash

2010-08-01

Language functions are known to be affected in diverse neurological conditions, including ischemic stroke, traumatic brain injury, and brain tumors. Because language networks are extensive, interpretation of functional data depends on the task completed during evaluation. The aim was to map the hemodynamic consequences of word association using functional magnetic resonance imaging (fMRI) in normal human subjects. Ten healthy subjects underwent fMRI scanning with a postlexical access semantic association task vs lexical processing task. The fMRI protocol involved a T2*-weighted gradient-echo echo-planar imaging (GE-EPI) sequence (TR 4523 ms, TE 64 ms, flip angle 90°) with alternate baseline and activation blocks. A total of 78 scans were taken (interscan interval = 3 s) with a total imaging time of 587 s. Functional data were processed in Statistical Parametric Mapping software (SPM2) with 8-mm Gaussian kernel by convolving the blood oxygenation level-dependent (BOLD) signal with an hemodynamic response function estimated by general linear method to generate SPM{t} and SPM{F} maps. Single subject analysis of the functional data (FWE-corrected, P≤0.001) revealed extensive activation in the frontal lobes, with overlaps among middle frontal gyrus (MFG), superior, and inferior frontal gyri. BOLD activity was also found in the medial frontal gyrus, middle occipital gyrus (MOG), anterior fusiform gyrus, superior and inferior parietal lobules, and to a smaller extent, the thalamus and right anterior cerebellum. Group analysis (FWE-corrected, P≤0.001) revealed neural recruitment of bilateral lingual gyri, left MFG, bilateral MOG, left superior occipital gyrus, left fusiform gyrus, bilateral thalami, and right cerebellar areas. Group data analysis revealed a cerebellar-occipital-fusiform-thalamic network centered around bilateral lingual gyri for word association, thereby indicating how these areas facilitate language comprehension by activating a semantic association network of words processed postlexical access. This finding is important when assessing the extent of cognitive damage and/or recovery and can be used for presurgical planning after optimization.

Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

PubMed

Kropp, Peter A; Dunn, Jennifer C; Carboneau, Bethany A; Stoffers, Doris A; Gannon, Maureen

2018-04-01

The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.

Platelet proteome reveals novel pathways of platelet activation and platelet-mediated immunoregulation in dengue.

PubMed

Trugilho, Monique Ramos de Oliveira; Hottz, Eugenio Damaceno; Brunoro, Giselle Villa Flor; Teixeira-Ferreira, André; Carvalho, Paulo Costa; Salazar, Gustavo Adolfo; Zimmerman, Guy A; Bozza, Fernando A; Bozza, Patrícia T; Perales, Jonas

2017-05-01

Dengue is the most prevalent human arbovirus disease worldwide. Dengue virus (DENV) infection causes syndromes varying from self-limiting febrile illness to severe dengue. Although dengue pathophysiology is not completely understood, it is widely accepted that increased inflammation plays important roles in dengue pathogenesis. Platelets are blood cells classically known as effectors of hemostasis which have been increasingly recognized to have major immune and inflammatory activities. Nevertheless, the phenotype and effector functions of platelets in dengue pathogenesis are not completely understood. Here we used quantitative proteomics to investigate the protein content of platelets in clinical samples from patients with dengue compared to platelets from healthy donors. Our assays revealed a set of 252 differentially abundant proteins. In silico analyses associated these proteins with key molecular events including platelet activation and inflammatory responses, and with events not previously attributed to platelets during dengue infection including antigen processing and presentation, proteasome activity, and expression of histones. From these results, we conducted functional assays using samples from a larger cohort of patients and demonstrated evidence for platelet activation indicated by P-selectin (CD62P) translocation and secretion of granule-stored chemokines by platelets. In addition, we found evidence that DENV infection triggers HLA class I synthesis and surface expression by a mechanism depending on functional proteasome activity. Furthermore, we demonstrate that cell-free histone H2A released during dengue infection binds to platelets, increasing platelet activation. These findings are consistent with functional importance of HLA class I, proteasome subunits, and histones that we found exclusively in proteome analysis of platelets in samples from dengue patients. Our study provides the first in-depth characterization of the platelet proteome in dengue, and sheds light on new mechanisms of platelet activation and platelet-mediated immune and inflammatory responses.

Working Memory in the Prefrontal Cortex

PubMed Central

Funahashi, Shintaro

2017-01-01

The prefrontal cortex participates in a variety of higher cognitive functions. The concept of working memory is now widely used to understand prefrontal functions. Neurophysiological studies have revealed that stimulus-selective delay-period activity is a neural correlate of the mechanism for temporarily maintaining information in working memory processes. The central executive, which is the master component of Baddeley’s working memory model and is thought to be a function of the prefrontal cortex, controls the performance of other components by allocating a limited capacity of memory resource to each component based on its demand. Recent neurophysiological studies have attempted to reveal how prefrontal neurons achieve the functions of the central executive. For example, the neural mechanisms of memory control have been examined using the interference effect in a dual-task paradigm. It has been shown that this interference effect is caused by the competitive and overloaded recruitment of overlapping neural populations in the prefrontal cortex by two concurrent tasks and that the information-processing capacity of a single neuron is limited to a fixed level, can be flexibly allocated or reallocated between two concurrent tasks based on their needs, and enhances behavioral performance when its allocation to one task is increased. Further, a metamemory task requiring spatial information has been used to understand the neural mechanism for monitoring its own operations, and it has been shown that monitoring the quality of spatial information represented by prefrontal activity is an important factor in the subject's choice and that the strength of spatially selective delay-period activity reflects confidence in decision-making. Although further studies are needed to elucidate how the prefrontal cortex controls memory resource and supervises other systems, some important mechanisms related to the central executive have been identified. PMID:28448453

Platelet proteome reveals novel pathways of platelet activation and platelet-mediated immunoregulation in dengue

PubMed Central

Teixeira-Ferreira, André; Carvalho, Paulo Costa; Salazar, Gustavo Adolfo; Zimmerman, Guy A.; Perales, Jonas

2017-01-01

Dengue is the most prevalent human arbovirus disease worldwide. Dengue virus (DENV) infection causes syndromes varying from self-limiting febrile illness to severe dengue. Although dengue pathophysiology is not completely understood, it is widely accepted that increased inflammation plays important roles in dengue pathogenesis. Platelets are blood cells classically known as effectors of hemostasis which have been increasingly recognized to have major immune and inflammatory activities. Nevertheless, the phenotype and effector functions of platelets in dengue pathogenesis are not completely understood. Here we used quantitative proteomics to investigate the protein content of platelets in clinical samples from patients with dengue compared to platelets from healthy donors. Our assays revealed a set of 252 differentially abundant proteins. In silico analyses associated these proteins with key molecular events including platelet activation and inflammatory responses, and with events not previously attributed to platelets during dengue infection including antigen processing and presentation, proteasome activity, and expression of histones. From these results, we conducted functional assays using samples from a larger cohort of patients and demonstrated evidence for platelet activation indicated by P-selectin (CD62P) translocation and secretion of granule-stored chemokines by platelets. In addition, we found evidence that DENV infection triggers HLA class I synthesis and surface expression by a mechanism depending on functional proteasome activity. Furthermore, we demonstrate that cell-free histone H2A released during dengue infection binds to platelets, increasing platelet activation. These findings are consistent with functional importance of HLA class I, proteasome subunits, and histones that we found exclusively in proteome analysis of platelets in samples from dengue patients. Our study provides the first in-depth characterization of the platelet proteome in dengue, and sheds light on new mechanisms of platelet activation and platelet-mediated immune and inflammatory responses. PMID:28542641

Individual-based analyses reveal limited functional overlap in a coral reef fish community.

PubMed

Brandl, Simon J; Bellwood, David R

2014-05-01

Detailed knowledge of a species' functional niche is crucial for the study of ecological communities and processes. The extent of niche overlap, functional redundancy and functional complementarity is of particular importance if we are to understand ecosystem processes and their vulnerability to disturbances. Coral reefs are among the most threatened marine systems, and anthropogenic activity is changing the functional composition of reefs. The loss of herbivorous fishes is particularly concerning as the removal of algae is crucial for the growth and survival of corals. Yet, the foraging patterns of the various herbivorous fish species are poorly understood. Using a multidimensional framework, we present novel individual-based analyses of species' realized functional niches, which we apply to a herbivorous coral reef fish community. In calculating niche volumes for 21 species, based on their microhabitat utilization patterns during foraging, and computing functional overlaps, we provide a measurement of functional redundancy or complementarity. Complementarity is the inverse of redundancy and is defined as less than 50% overlap in niche volumes. The analyses reveal extensive complementarity with an average functional overlap of just 15.2%. Furthermore, the analyses divide herbivorous reef fishes into two broad groups. The first group (predominantly surgeonfishes and parrotfishes) comprises species feeding on exposed surfaces and predominantly open reef matrix or sandy substrata, resulting in small niche volumes and extensive complementarity. In contrast, the second group consists of species (predominantly rabbitfishes) that feed over a wider range of microhabitats, penetrating the reef matrix to exploit concealed surfaces of various substratum types. These species show high variation among individuals, leading to large niche volumes, more overlap and less complementarity. These results may have crucial consequences for our understanding of herbivorous processes on coral reefs, as algal removal appears to depend strongly on species-specific microhabitat utilization patterns of herbivores. Furthermore, the results emphasize the capacity of the individual-based analyses to reveal variation in the functional niches of species, even in high-diversity systems such as coral reefs, demonstrating its potential applicability to other high-diversity ecosystems. © 2013 The Authors. Journal of Animal Ecology © 2013 British Ecological Society.

Co-regulation of Iron Metabolism and Virulence Associated Functions by Iron and XibR, a Novel Iron Binding Transcription Factor, in the Plant Pathogen Xanthomonas

PubMed Central

Pandey, Sheo Shankar; Patnana, Pradeep Kumar; Lomada, Santosh Kumar; Tomar, Archana; Chatterjee, Subhadeep

2016-01-01

Abilities of bacterial pathogens to adapt to the iron limitation present in hosts is critical to their virulence. Bacterial pathogens have evolved diverse strategies to coordinately regulate iron metabolism and virulence associated functions to maintain iron homeostasis in response to changing iron availability in the environment. In many bacteria the ferric uptake regulator (Fur) functions as transcription factor that utilize ferrous form of iron as cofactor to regulate transcription of iron metabolism and many cellular functions. However, mechanisms of fine-tuning and coordinated regulation of virulence associated function beyond iron and Fur-Fe2+ remain undefined. In this study, we show that a novel transcriptional regulator XibR (named X anthomonas iron binding regulator) of the NtrC family, is required for fine-tuning and co-coordinately regulating the expression of several iron regulated genes and virulence associated functions in phytopathogen Xanthomonas campestris pv. campestris (Xcc). Genome wide expression analysis of iron-starvation stimulon and XibR regulon, GUS assays, genetic and functional studies of xibR mutant revealed that XibR positively regulates functions involved in iron storage and uptake, chemotaxis, motility and negatively regulates siderophore production, in response to iron. Furthermore, chromatin immunoprecipitation followed by quantitative real-time PCR indicated that iron promoted binding of the XibR to the upstream regulatory sequence of operon’s involved in chemotaxis and motility. Circular dichroism spectroscopy showed that purified XibR bound ferric form of iron. Electrophoretic mobility shift assay revealed that iron positively affected the binding of XibR to the upstream regulatory sequences of the target virulence genes, an effect that was reversed by ferric iron chelator deferoxamine. Taken together, these data revealed that how XibR coordinately regulates virulence associated and iron metabolism functions in Xanthomonads in response to iron availability. Our results provide insight of the complex regulatory mechanism of fine-tuning of virulence associated functions with iron availability in this important group of phytopathogen. PMID:27902780

The well-coordinated linkage between acidogenicity and aciduricity via insoluble glucans on the surface of Streptococcus mutans

PubMed Central

Guo, Lihong; McLean, Jeffrey S.; Lux, Renate; He, Xuesong; Shi, Wenyuan

2015-01-01

Streptococcus mutans is considered the principal cariogenic bacterium for dental caries. Despite the recognition of their importance for cariogenesis, the possible coordination among S. mutans’ main virulence factors, including glucan production, acidogenicity and aciduricity, has been less well studied. In the present study, using S. mutans strains with surface-displayed pH-sensitive pHluorin, we revealed sucrose availability- and Gtf functionality-dependent proton accumulation on S. mutans surface. Consistent with this, using a pH-sensitive dye, we demonstrated that both in vivo cell-produced and in vitro enzymatically synthesized insoluble glucans displayed proton-concentrating ability. Global transcriptomics revealed proton accumulation triggers the up-regulation of genes encoding functions involved in acid tolerance response in a glucan-dependent manner. Our data suggested that this proton enrichment around S. mutans could pre-condition the bacterium for acid-stress. Consistent with this hypothesis, we found S. mutans strains defective in glucan production were more acid sensitive. Our study revealed for the first time that insoluble glucans is likely an essential factor linking acidogenicity with aciduricity. The coordination of these key virulence factors could provide new insights on how S. mutans may have become a major cariogenic pathogen. PMID:26657939

Comparison of Saccharomyces cerevisiae F-BAR domain structures reveals a conserved inositol phosphate binding site.

PubMed

Moravcevic, Katarina; Alvarado, Diego; Schmitz, Karl R; Kenniston, Jon A; Mendrola, Jeannine M; Ferguson, Kathryn M; Lemmon, Mark A

2015-02-03

F-BAR domains control membrane interactions in endocytosis, cytokinesis, and cell signaling. Although they are generally thought to bind curved membranes containing negatively charged phospholipids, numerous functional studies argue that differences in lipid-binding selectivities of F-BAR domains are functionally important. Here, we compare membrane-binding properties of the Saccharomyces cerevisiae F-BAR domains in vitro and in vivo. Whereas some F-BAR domains (such as Bzz1p and Hof1p F-BARs) bind equally well to all phospholipids, the F-BAR domain from the RhoGAP Rgd1p preferentially binds phosphoinositides. We determined X-ray crystal structures of F-BAR domains from Hof1p and Rgd1p, the latter bound to an inositol phosphate. The structures explain phospholipid-binding selectivity differences and reveal an F-BAR phosphoinositide binding site that is fully conserved in a mammalian RhoGAP called Gmip and is partly retained in certain other F-BAR domains. Our findings reveal previously unappreciated determinants of F-BAR domain lipid-binding specificity and provide a basis for its prediction from sequence. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development.

PubMed

Bonilla-Claudio, Margarita; Wang, Jun; Bai, Yan; Klysik, Elzbieta; Selever, Jennifer; Martin, James F

2012-02-01

We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmp-regulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors.

Structural, functional and pH sensitive release characteristics of water-soluble polysaccharide from the seeds of Albizia lebbeck L.

PubMed

Kumar Varma, Chekuri Ashok; Jayaram Kumar, K

2017-11-01

Plant polysaccharides, generally regarded as safe (GRAS), are gaining importance as excipients in drug delivery. Therefore, the current paper presents the studies on structural, functional and drug release study of water soluble polysaccharide (ALPS) from seeds of Albizia lebbeck L. High swelling, water holding capacity, foam stability and lower moisture content suggests its use as additive in food preparations. The apparent molecular weight of polysaccharide was found to be 1.98×10 2 kDa. Monosaccharide composition analysis indicated that ALPS consists of mannose (4.06%), rhamnose (22.79%), glucose (38.9%), galactose (17.84%) and xylose (16.42%). Micromeritic properties revealed that the polysaccharide possess potential for pharmaceutical applications. From the surface charge analysis, ALPS was found to be non-ionic polysaccharide. Morphological study reveals the polysaccharide with irregular particle shape and rough surface. Fourier transformed infrared spectroscopy (FTIR) study confirms the carbohydrate nature of polysaccharide. From the thermogravimetric analysis (TGA) data, the second mass loss (243-340°C) attributed to polysaccharide degradation. The drug release profile reveals the use of polysaccharide for the preparation of pH sensitive pharmaceutical dosage forms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain*S⃞

PubMed Central

Bottomley, Matthew J.; Lo Surdo, Paola; Di Giovine, Paolo; Cirillo, Agostino; Scarpelli, Rita; Ferrigno, Federica; Jones, Philip; Neddermann, Petra; De Francesco, Raffaele; Steinkühler, Christian; Gallinari, Paola; Carfí, Andrea

2008-01-01

Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR·HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions. PMID:18614528

Comparison of Saccharomyces cerevisiae F-BAR Domain Structures Reveals a Conserved Inositol Phosphate Binding Site

DOE PAGES

Moravcevic, Katarina; Alvarado, Diego; Schmitz, Karl R.; ...

2015-01-22

F-BAR domains control membrane interactions in endocytosis, cytokinesis, and cell signaling. Although they are generally thought to bind curved membranes containing negatively charged phospholipids, numerous functional studies argue that differences in lipid-binding selectivities of F-BAR domains are functionally important. Here in this paper, we compare membrane-binding properties of the Saccharomyces cerevisiae F-BAR domains in vitro and in vivo. Whereas some F-BAR domains (such as Bzz1p and Hof1p F-BARs) bind equally well to all phospholipids, the F-BAR domain from the RhoGAP Rgd1p preferentially binds phosphoinositides. We determined X-ray crystal structures of F-BAR domains from Hof1p and Rgd1p, the latter bound tomore » an inositol phosphate. The structures explain phospholipid-binding selectivity differences and reveal an F-BAR phosphoinositide binding site that is fully conserved in a mammalian RhoGAP called Gmip and is partly retained in certain other F-BAR domains. In conclusion, our findings reveal previously unappreciated determinants of F-BAR domain lipid-binding specificity and provide a basis for its prediction from sequence.« less

The innate capacity of proteins to protect against reactive radical species.

PubMed

Hamdy, Omar M; Alizadeh, Arman; Julian, Ryan R

2015-08-07

Maintaining redox homeostasis, or the balance of oxidant and antioxidant forces, is essential for proper cellular functioning in biology. Although the antioxidant nature of many small molecules such as vitamin c and glutathione have been thoroughly investigated, contributions to redox homeostasis from larger biomolecules have received less attention. Evidence has shown that some proteins are antioxidant (in a non-catalytic sense), but large scale examination of this property for a diverse set of proteins has proven difficult. Herein, radical-directed dissociation mass spectrometry (RDD-MS) is used to examine the antioxidant capacity of a series of proteins with diverse biological roles, persistence intervals, and localizations. Digestion of these proteins reveals that all contain antioxidant peptide regions. Examination of the amino acid content of the antioxidant peptides does not reveal significant differences relative to normal peptides, suggesting that sequence may be more important than residue content. Sequence homology analysis across organisms reveals that antioxidant regions are frequently conserved, although many of these regions are also known to have other functions which may have influenced evolutionary pressure. Regardless of the origin, it is clear that many proteins may play secondary roles as sacrificial antioxidants within the cellular milieu.

Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.

PubMed

Bottomley, Matthew J; Lo Surdo, Paola; Di Giovine, Paolo; Cirillo, Agostino; Scarpelli, Rita; Ferrigno, Federica; Jones, Philip; Neddermann, Petra; De Francesco, Raffaele; Steinkühler, Christian; Gallinari, Paola; Carfí, Andrea

2008-09-26

Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.

Global analyses of Ceratocystis cacaofunesta mitochondria: from genome to proteome.

PubMed

Ambrosio, Alinne Batista; do Nascimento, Leandro Costa; Oliveira, Bruno V; Teixeira, Paulo José P L; Tiburcio, Ricardo A; Toledo Thomazella, Daniela P; Leme, Adriana F P; Carazzolle, Marcelo F; Vidal, Ramon O; Mieczkowski, Piotr; Meinhardt, Lyndel W; Pereira, Gonçalo A G; Cabrera, Odalys G

2013-02-11

The ascomycete fungus Ceratocystis cacaofunesta is the causal agent of wilt disease in cacao, which results in significant economic losses in the affected producing areas. Despite the economic importance of the Ceratocystis complex of species, no genomic data are available for any of its members. Given that mitochondria play important roles in fungal virulence and the susceptibility/resistance of fungi to fungicides, we performed the first functional analysis of this organelle in Ceratocystis using integrated "omics" approaches. The C. cacaofunesta mitochondrial genome (mtDNA) consists of a single, 103,147-bp circular molecule, making this the second largest mtDNA among the Sordariomycetes. Bioinformatics analysis revealed the presence of 15 conserved genes and 37 intronic open reading frames in C. cacaofunesta mtDNA. Here, we predicted the mitochondrial proteome (mtProt) of C. cacaofunesta, which is comprised of 1,124 polypeptides - 52 proteins that are mitochondrially encoded and 1,072 that are nuclearly encoded. Transcriptome analysis revealed 33 probable novel genes. Comparisons among the Gene Ontology results of the predicted mtProt of C. cacaofunesta, Neurospora crassa and Saccharomyces cerevisiae revealed no significant differences. Moreover, C. cacaofunesta mitochondria were isolated, and the mtProt was subjected to mass spectrometric analysis. The experimental proteome validated 27% of the predicted mtProt. Our results confirmed the existence of 110 hypothetical proteins and 7 novel proteins of which 83 and 1, respectively, had putative mitochondrial localization. The present study provides the first partial genomic analysis of a species of the Ceratocystis genus and the first predicted mitochondrial protein inventory of a phytopathogenic fungus. In addition to the known mitochondrial role in pathogenicity, our results demonstrated that the global function analysis of this organelle is similar in pathogenic and non-pathogenic fungi, suggesting that its relevance in the lifestyle of these organisms should be based on a small number of specific proteins and/or with respect to differential gene regulation. In this regard, particular interest should be directed towards mitochondrial proteins with unknown function and the novel protein that might be specific to this species. Further functional characterization of these proteins could enhance our understanding of the role of mitochondria in phytopathogenicity.

Global analyses of Ceratocystis cacaofunesta mitochondria: from genome to proteome

PubMed Central

2013-01-01

Background The ascomycete fungus Ceratocystis cacaofunesta is the causal agent of wilt disease in cacao, which results in significant economic losses in the affected producing areas. Despite the economic importance of the Ceratocystis complex of species, no genomic data are available for any of its members. Given that mitochondria play important roles in fungal virulence and the susceptibility/resistance of fungi to fungicides, we performed the first functional analysis of this organelle in Ceratocystis using integrated “omics” approaches. Results The C. cacaofunesta mitochondrial genome (mtDNA) consists of a single, 103,147-bp circular molecule, making this the second largest mtDNA among the Sordariomycetes. Bioinformatics analysis revealed the presence of 15 conserved genes and 37 intronic open reading frames in C. cacaofunesta mtDNA. Here, we predicted the mitochondrial proteome (mtProt) of C. cacaofunesta, which is comprised of 1,124 polypeptides - 52 proteins that are mitochondrially encoded and 1,072 that are nuclearly encoded. Transcriptome analysis revealed 33 probable novel genes. Comparisons among the Gene Ontology results of the predicted mtProt of C. cacaofunesta, Neurospora crassa and Saccharomyces cerevisiae revealed no significant differences. Moreover, C. cacaofunesta mitochondria were isolated, and the mtProt was subjected to mass spectrometric analysis. The experimental proteome validated 27% of the predicted mtProt. Our results confirmed the existence of 110 hypothetical proteins and 7 novel proteins of which 83 and 1, respectively, had putative mitochondrial localization. Conclusions The present study provides the first partial genomic analysis of a species of the Ceratocystis genus and the first predicted mitochondrial protein inventory of a phytopathogenic fungus. In addition to the known mitochondrial role in pathogenicity, our results demonstrated that the global function analysis of this organelle is similar in pathogenic and non-pathogenic fungi, suggesting that its relevance in the lifestyle of these organisms should be based on a small number of specific proteins and/or with respect to differential gene regulation. In this regard, particular interest should be directed towards mitochondrial proteins with unknown function and the novel protein that might be specific to this species. Further functional characterization of these proteins could enhance our understanding of the role of mitochondria in phytopathogenicity. PMID:23394930

Disturbed prefrontal and temporal brain function during emotion and cognition interaction in criminal psychopathy.

PubMed

Müller, Jürgen L; Sommer, Monika; Döhnel, Katrin; Weber, Tatjana; Schmidt-Wilcke, Tobias; Hajak, Göran

2008-01-01

Impaired emotional responsiveness has been revealed as a hallmark of psychopathy. In spite of an increasing database on emotion processing, studies on cognitive function and in particular on the impact of emotion on cognition in psychopathy are rare. We used pictures from the International Affective Picture Set (IAPS) and a Simon Paradigm to address emotion-cognition interaction while functional and structural imaging data were obtained in 12 healthy controls and 10 psychopaths. We found an impaired emotion-cognition interaction in psychopaths that correlated with a changed prefrontal and temporal brain activation. With regard to the temporal cortex, it is shown that structure and function of the right superior temporal gyrus is disturbed in psychopathy, supporting a neurobiological approach to psychopathy, in which structure and function of the right STG may be important. (c) 2008 John Wiley & Sons, Ltd.

The role of parenting in affecting the behavior and adaptive functioning of young children of HIV-infected mothers in South Africa.

PubMed

Allen, Alexandra Boeving; Finestone, Michelle; Eloff, Irma; Sipsma, Heather; Makin, Jennifer; Triplett, Kelli; Ebersöhn, Liesel; Sikkema, Kathleen; Briggs-Gowan, Margaret; Visser, Maretha; Ferreira, Ronél; Forsyth, Brian W C

2014-03-01

Prior investigations suggest that maternal HIV/AIDS poses significant challenges to young children. This study investigates the relationships between mothers' psychological functioning, parenting, and children's behavioral outcomes and functioning in a population of women living with HIV (N = 361) with a child between the ages of 6 and 10 years in Tshwane, South Africa. Utilizing path analysis, findings revealed that maternal depression is related to increased parenting stress and parent-child dysfunction, maternal coping is related to parenting style, and maternal coping, parenting style and stress, and parent-child dysfunction are associated with children's behavior and functioning, with parenting emerging as an important mediator. These findings suggest that interventions for women living with HIV and their children should not only address maternal psychological functioning (depression and coping), but should also focus on parenting, promoting a positive approach.

Robust validation of approximate 1-matrix functionals with few-electron harmonium atoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cioslowski, Jerzy, E-mail: jerzy@wmf.univ.szczecin.pl; Piris, Mario; Matito, Eduard

2015-12-07

A simple comparison between the exact and approximate correlation components U of the electron-electron repulsion energy of several states of few-electron harmonium atoms with varying confinement strengths provides a stringent validation tool for 1-matrix functionals. The robustness of this tool is clearly demonstrated in a survey of 14 known functionals, which reveals their substandard performance within different electron correlation regimes. Unlike spot-testing that employs dissociation curves of diatomic molecules or more extensive benchmarking against experimental atomization energies of molecules comprising some standard set, the present approach not only uncovers the flaws and patent failures of the functionals but, even moremore » importantly, also allows for pinpointing their root causes. Since the approximate values of U are computed at exact 1-densities, the testing requires minimal programming and thus is particularly suitable for rapid screening of new functionals.« less

Resolving Microzooplankton Functional Groups In A Size-Structured Planktonic Model

NASA Astrophysics Data System (ADS)

Taniguchi, D.; Dutkiewicz, S.; Follows, M. J.; Jahn, O.; Menden-Deuer, S.

2016-02-01

Microzooplankton are important marine grazers, often consuming a large fraction of primary productivity. They consist of a great diversity of organisms with different behaviors, characteristics, and rates. This functional diversity, and its consequences, are not currently reflected in large-scale ocean ecological simulations. How should these organisms be represented, and what are the implications for their biogeography? We develop a size-structured, trait-based model to characterize a diversity of microzooplankton functional groups. We compile and examine size-based laboratory data on the traits, revealing some patterns with size and functional group that we interpret with mechanistic theory. Fitting the model to the data provides parameterizations of key rates and properties, which we employ in a numerical ocean model. The diversity of grazing preference, rates, and trophic strategies enables the coexistence of different functional groups of micro-grazers under various environmental conditions, and the model produces testable predictions of the biogeography.

Identifying the distinct features of geometric structures for hole trapping to generate radicals on rutile TiO₂(110) in photooxidation using density functional theory calculations with hybrid functional.

PubMed

Wang, Dong; Wang, Haifeng; Hu, P

2015-01-21

Using density functional theory calculations with HSE 06 functional, we obtained the structures of spin-polarized radicals on rutile TiO2(110), which is crucial to understand the photooxidation at the atomic level, and further calculate the thermodynamic stabilities of these radicals. By analyzing the results, we identify the structural features for hole trapping in the system, and reveal the mutual effects among the geometric structures, the energy levels of trapped hole states and their hole trapping capacities. Furthermore, the results from HSE 06 functional are compared to those from DFT + U and the stability trend of radicals against the number of slabs is tested. The effect of trapped holes on two important steps of the oxygen evolution reaction, i.e. water dissociation and the oxygen removal, is investigated and discussed.

The Role of Parenting in Affecting the Behavior and Adaptive Functioning of Young Children of HIV-Infected Mothers in South Africa

PubMed Central

Allen, Alexandra Boeving; Finestone, Michelle; Sipsma, Heather; Makin, Jennifer; Triplett, Kelli; Ebersöhn, Liesel; Sikkema, Kathleen; Briggs-Gowan, Margaret; Visser, Maretha; Ferreira, Ronél; Forsyth, Brian W. C.

2013-01-01

Prior investigations suggest that maternal HIV/AIDS poses significant challenges to young children. This study investigates the relationships between mothers’ psychological functioning, parenting, and children’s behavioral outcomes and functioning in a population of women living with HIV (N = 361) with a child between the ages of 6 and 10 years in Tshwane, South Africa. Utilizing path analysis, findings revealed that maternal depression is related to increased parenting stress and parent–child dysfunction, maternal coping is related to parenting style, and maternal coping, parenting style and stress, and parent–child dysfunction are associated with children’s behavior and functioning, with parenting emerging as an important mediator. These findings suggest that interventions for women living with HIV and their children should not only address maternal psychological functioning (depression and coping), but should also focus on parenting, promoting a positive approach. PMID:23892768

Distinct hippocampal functional networks revealed by tractography-based parcellation.

PubMed

Adnan, Areeba; Barnett, Alexander; Moayedi, Massieh; McCormick, Cornelia; Cohn, Melanie; McAndrews, Mary Pat

2016-07-01

Recent research suggests the anterior and posterior hippocampus form part of two distinct functional neural networks. Here we investigate the structural underpinnings of this functional connectivity difference using diffusion-weighted imaging-based parcellation. Using this technique, we substantiated that the hippocampus can be parcellated into distinct anterior and posterior segments. These structurally defined segments did indeed show different patterns of resting state functional connectivity, in that the anterior segment showed greater connectivity with temporal and orbitofrontal cortex, whereas the posterior segment was more highly connected to medial and lateral parietal cortex. Furthermore, we showed that the posterior hippocampal connectivity to memory processing regions, including the dorsolateral prefrontal cortex, parahippocampal, inferior temporal and fusiform gyri and the precuneus, predicted interindividual relational memory performance. These findings provide important support for the integration of structural and functional connectivity in understanding the brain networks underlying episodic memory.

Amygdala subnuclei connectivity in response to violence reveals unique influences of individual differences in psychopathic traits in a non-forensic sample

PubMed Central

Yoder, Keith J.; Porges, Eric C.; Decety, Jean

2016-01-01

Atypical amygdala function and connectivity have reliably been associated with psychopathy. However, the amygdala is not a unitary structure. To examine how psychopathic traits in a non-forensic sample are linked to amygdala response to violence, the current study used probabilistic tractography to classify amygdala subnuclei based on anatomical projections to and from amygdala subnuclei in a group of 43 male participants. The segmentation identified the basolateral complex (BLA; lateral, basal, and accessory basal subnuclei) and the central subnucleus (CE), which were used as seeds in a functional connectivity analysis to identify differences in neuronal coupling specific to observed violence. While a full amygdala seed showed significant connectivity only to right middle occipital gyrus, subnuclei seeds revealed unique connectivity patterns. BLA showed enhanced coupling with anterior cingulate and prefrontal regions, while CE showed increased connectivity with the brainstem, but reduced connectivity with superior parietal and precentral gyrus. Further, psychopathic personality factors were related to specific patterns of connectivity. Fearless Dominance scores on the psychopathic personality inventory predicted increased coupling between the BLA seed and sensory integration cortices, and increased connectivity between the CE seed and posterior insula. Conversely, Self-Centered Impulsivity scores were negatively correlated with coupling between BLA and ventrolateral prefrontal cortex, and Coldheartedness scores predicted increased functional connectivity between BLA and dorsal anterior cingulate cortex. Taken together, these findings demonstrate how subnuclei segmentations reveal important functional connectivity differences that are otherwise inaccessible. Such an approach yields a better understanding of amygdala dysfunction in psychopathy. PMID:25557777

Amygdala subnuclei connectivity in response to violence reveals unique influences of individual differences in psychopathic traits in a nonforensic sample.

PubMed

Yoder, Keith J; Porges, Eric C; Decety, Jean

2015-04-01

Atypical amygdala function and connectivity have reliably been associated with psychopathy. However, the amygdala is not a unitary structure. To examine how psychopathic traits in a nonforensic sample are linked to amygdala response to violence, this study used probabilistic tractography to classify amygdala subnuclei based on anatomical projections to and from amygdala subnuclei in a group of 43 male participants. The segmentation identified the basolateral complex (BLA; lateral, basal, and accessory basal subnuclei) and the central subnucleus (CE), which were used as seeds in a functional connectivity analysis to identify differences in neuronal coupling specific to observed violence. While a full amygdala seed showed significant connectivity only to right middle occipital gyrus, subnuclei seeds revealed unique connectivity patterns. BLA showed enhanced coupling with anterior cingulate and prefrontal regions, while CE showed increased connectivity with the brainstem, but reduced connectivity with superior parietal and precentral gyrus. Further, psychopathic personality factors were related to specific patterns of connectivity. Fearless Dominance scores on the psychopathic personality inventory predicted increased coupling between the BLA seed and sensory integration cortices, and increased connectivity between the CE seed and posterior insula. Conversely, Self-Centered Impulsivity scores were negatively correlated with coupling between BLA and ventrolateral prefrontal cortex, and Coldheartedness scores predicted increased functional connectivity between BLA and dorsal anterior cingulate cortex. Taken together, these findings demonstrate how subnuclei segmentations reveal important functional connectivity differences that are otherwise inaccessible. Such an approach yields a better understanding of amygdala dysfunction in psychopathy. © 2014 Wiley Periodicals, Inc.

Analysis of structure-function network decoupling in the brain systems of spastic diplegic cerebral palsy.

PubMed

Lee, Dongha; Pae, Chongwon; Lee, Jong Doo; Park, Eun Sook; Cho, Sung-Rae; Um, Min-Hee; Lee, Seung-Koo; Oh, Maeng-Keun; Park, Hae-Jeong

2017-10-01

Manifestation of the functionalities from the structural brain network is becoming increasingly important to understand a brain disease. With the aim of investigating the differential structure-function couplings according to network systems, we investigated the structural and functional brain networks of patients with spastic diplegic cerebral palsy with periventricular leukomalacia compared to healthy controls. The structural and functional networks of the whole brain and motor system, constructed using deterministic and probabilistic tractography of diffusion tensor magnetic resonance images and Pearson and partial correlation analyses of resting-state functional magnetic resonance images, showed differential embedding of functional networks in the structural networks in patients. In the whole-brain network of patients, significantly reduced global network efficiency compared to healthy controls were found in the structural networks but not in the functional networks, resulting in reduced structural-functional coupling. On the contrary, the motor network of patients had a significantly lower functional network efficiency over the intact structural network and a lower structure-function coupling than the control group. This reduced coupling but reverse directionality in the whole-brain and motor networks of patients was prominent particularly between the probabilistic structural and partial correlation-based functional networks. Intact (or less deficient) functional network over impaired structural networks of the whole brain and highly impaired functional network topology over the intact structural motor network might subserve relatively preserved cognitions and impaired motor functions in cerebral palsy. This study suggests that the structure-function relationship, evaluated specifically using sparse functional connectivity, may reveal important clues to functional reorganization in cerebral palsy. Hum Brain Mapp 38:5292-5306, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Transcriptome-wide analysis of WRKY transcription factors in wheat and their leaf rust responsive expression profiling.

PubMed

Satapathy, Lopamudra; Singh, Dharmendra; Ranjan, Prashant; Kumar, Dhananjay; Kumar, Manish; Prabhu, Kumble Vinod; Mukhopadhyay, Kunal

2014-12-01

WRKY, a plant-specific transcription factor family, has important roles in pathogen defense, abiotic cues and phytohormone signaling, yet little is known about their roles and molecular mechanism of function in response to rust diseases in wheat. We identified 100 TaWRKY sequences using wheat Expressed Sequence Tag database of which 22 WRKY sequences were novel. Identified proteins were characterized based on their zinc finger motifs and phylogenetic analysis clustered them into six clades consisting of class IIc and class III WRKY proteins. Functional annotation revealed major functions in metabolic and cellular processes in control plants; whereas response to stimuli, signaling and defense in pathogen inoculated plants, their major molecular function being binding to DNA. Tag-based expression analysis of the identified genes revealed differential expression between mock and Puccinia triticina inoculated wheat near isogenic lines. Gene expression was also performed with six rust-related microarray experiments at Gene Expression Omnibus database. TaWRKY10, 15, 17 and 56 were common in both tag-based and microarray-based differential expression analysis and could be representing rust specific WRKY genes. The obtained results will bestow insight into the functional characterization of WRKY transcription factors responsive to leaf rust pathogenesis that can be used as candidate genes in molecular breeding programs to improve biotic stress tolerance in wheat.

Novel cis-acting element within the capsid-coding region enhances flavivirus viral-RNA replication by regulating genome cyclization.

PubMed

Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Zhao, Hui; Wang, Hong-Jiang; Ye, Qing; Zhu, Shun-Ya; Qiu, Yang; Zhou, Xi; Qin, E-De; Qin, Cheng-Feng

2013-06-01

cis-Acting elements in the viral genome RNA (vRNA) are essential for the translation, replication, and/or encapsidation of RNA viruses. In this study, a novel conserved cis-acting element was identified in the capsid-coding region of mosquito-borne flavivirus. The downstream of 5' cyclization sequence (5'CS) pseudoknot (DCS-PK) element has a three-stem pseudoknot structure, as demonstrated by structure prediction and biochemical analysis. Using dengue virus as a model, we show that DCS-PK enhances vRNA replication and that its function depends on its secondary structure and specific primary sequence. Mutagenesis revealed that the highly conserved stem 1 and loop 2, which are involved in potential loop-helix interactions, are crucial for DCS-PK function. A predicted loop 1-stem 3 base triple interaction is important for the structural stability and function of DCS-PK. Moreover, the function of DCS-PK depends on its position relative to the 5'CS, and the presence of DCS-PK facilitates the formation of 5'-3' RNA complexes. Taken together, our results reveal that the cis-acting element DCS-PK enhances vRNA replication by regulating genome cyclization, and DCS-PK might interplay with other cis-acting elements to form a functional vRNA cyclization domain, thus playing critical roles during the flavivirus life cycle and evolution.

Novel cis-Acting Element within the Capsid-Coding Region Enhances Flavivirus Viral-RNA Replication by Regulating Genome Cyclization

PubMed Central

Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Zhao, Hui; Wang, Hong-Jiang; Ye, Qing; Zhu, Shun-Ya; Qiu, Yang; Zhou, Xi; Qin, E-De

2013-01-01

cis-Acting elements in the viral genome RNA (vRNA) are essential for the translation, replication, and/or encapsidation of RNA viruses. In this study, a novel conserved cis-acting element was identified in the capsid-coding region of mosquito-borne flavivirus. The downstream of 5′ cyclization sequence (5′CS) pseudoknot (DCS-PK) element has a three-stem pseudoknot structure, as demonstrated by structure prediction and biochemical analysis. Using dengue virus as a model, we show that DCS-PK enhances vRNA replication and that its function depends on its secondary structure and specific primary sequence. Mutagenesis revealed that the highly conserved stem 1 and loop 2, which are involved in potential loop-helix interactions, are crucial for DCS-PK function. A predicted loop 1-stem 3 base triple interaction is important for the structural stability and function of DCS-PK. Moreover, the function of DCS-PK depends on its position relative to the 5′CS, and the presence of DCS-PK facilitates the formation of 5′-3′ RNA complexes. Taken together, our results reveal that the cis-acting element DCS-PK enhances vRNA replication by regulating genome cyclization, and DCS-PK might interplay with other cis-acting elements to form a functional vRNA cyclization domain, thus playing critical roles during the flavivirus life cycle and evolution. PMID:23576500

Microbial Communities and Functional Genes Associated with Soil Arsenic Contamination and the Rhizosphere of the Arsenic-Hyperaccumulating Plant Pteris vittata L. ▿ †

PubMed Central

Xiong, Jinbo; Wu, Liyou; Tu, Shuxin; Van Nostrand, Joy D.; He, Zhili; Zhou, Jizhong; Wang, Gejiao

2010-01-01

To understand how microbial communities and functional genes respond to arsenic contamination in the rhizosphere of Pteris vittata, five soil samples with different arsenic contamination levels were collected from the rhizosphere of P. vittata and nonrhizosphere areas and investigated by Biolog, geochemical, and functional gene microarray (GeoChip 3.0) analyses. Biolog analysis revealed that the uncontaminated soil harbored the greatest diversity of sole-carbon utilization abilities and that arsenic contamination decreased the metabolic diversity, while rhizosphere soils had higher metabolic diversities than did the nonrhizosphere soils. GeoChip 3.0 analysis showed low proportions of overlapping genes across the five soil samples (16.52% to 45.75%). The uncontaminated soil had a higher heterogeneity and more unique genes (48.09%) than did the arsenic-contaminated soils. Arsenic resistance, sulfur reduction, phosphorus utilization, and denitrification genes were remarkably distinct between P. vittata rhizosphere and nonrhizosphere soils, which provides evidence for a strong linkage among the level of arsenic contamination, the rhizosphere, and the functional gene distribution. Canonical correspondence analysis (CCA) revealed that arsenic is the main driver in reducing the soil functional gene diversity; however, organic matter and phosphorus also have significant effects on the soil microbial community structure. The results implied that rhizobacteria play an important role during soil arsenic uptake and hyperaccumulation processes of P. vittata. PMID:20833780

Genome-wide STAT3 binding analysis after histone deacetylase inhibition reveals novel target genes in dendritic cells

PubMed Central

Sun, Yaping; Iyer, Matthew; McEachin, Richard; Zhao, Meng; Wu, Yi-Mi; Cao, Xuhong; Oravecz-Wilson, Katherine; Zajac, Cynthia; Mathewson, Nathan; Wu, Shin-Rong Julia; Rossi, Corinne; Toubai, Tomomi; Qin, Zhaohui S.; Chinnaiya, Arul M.; Reddy, Pavan

2016-01-01

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP-seq coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of non-canonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of pro-inflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition. PMID:27866206

The role of decision-making ability in HIV/AIDS: impact on prospective memory.

PubMed

Coulehan, Kelly; Byrd, Desiree; Arentoft, Alyssa; Monzones, Jennifer; Fuentes, Armando; Fraser, Felicia; Rosario, Ana; Morgello, Susan; Mindt, Monica Rivera

2014-01-01

Prospective memory (ProM), a form of episodic memory related to execution of future intentions, is important for everyday functioning. Among persons living with HIV (PLWH), executive dysfunction is implicated in ProM impairments. However, specific subcomponents of executive functioning involved in ProM deficits remain poorly understood. Unlike more "traditional" neurocognitive (NC) measures of executive functioning associated with dorsolateral prefrontal cortex (i.e., conceptual reasoning, abstraction), those associated with medial orbitofrontal/ventromedial prefrontal (mOF/vmP) cortex (i.e., decision making, inhibitory control, goal-oriented behavior) have yet to be examined in ProM. This study characterized ProM ability in a sample of 89 HIV-seropositive adults and examined the unique role of decision-making ability in ProM. Participants completed a standard NC battery, the Iowa Gambling Task (IGT; a decision-making measure), and the Memory for Intentions Screening Test (MIST; a ProM measure). Correlational analyses revealed that both traditional executive functioning measures and the IGT were associated with ProM. Regression analyses revealed that the IGT significantly predicted ProM, even after accounting for NC measures. Among all NC measures, only executive functioning significantly contributed to ProM. Further examination of mOF/vmP-sensitive executive dysfunction within this population is needed as PLWH may require more tailored treatment recommendations due to specific decision-making difficulties that can impact medication management.

Upper secondary and first-year university students' explanations of animal behaviour: to what extent are Tinbergen's four questions about causation, ontogeny, function and evolution, represented?

NASA Astrophysics Data System (ADS)

Pinxten, Rianne; Desclée, Mathieu; Eens, Marcel

2016-09-01

In 1963, the Nobel Prize-winning ethologist Niko Tinbergen proposed a framework for the scientific study of animal behaviour by outlining four questions that should be answered to have a complete understanding: causation, ontogeny, function and evolution. At present, Tinbergen's framework is still considered the best way to guide animal behavioural research. Given the importance in science instruction of demonstrating how scientists work and ask questions, we investigated to what extent Tinbergen's questions are addressed in biology textbooks in secondary education in Flanders, Belgium, and represented in upper-secondary and first-year university students' explanations of behaviour in general and of specific animal behaviours. Our results revealed that teaching of animal behaviour mainly addresses ontogeny and causation, and that Tinbergen's framework is not explicitly referred to. Students typically addressed only one or two questions, with the majority addressing causation or both causation and ontogeny when explaining behaviour in general, but function or causation and function when explaining specific animal behaviours. This high prevalence of function may be due to teleological thinking. Evolution was completely neglected, even in university students who had recently completed an evolution course. Our results revealed that transfer of the concepts of ontogeny and evolution was (almost) absent. We argue why Tinbergen's framework should be an integral part of any biology curriculum.

Exploration of the Energy Landscape of Acetylcholinesterase by Molecular Dynamics Simulation.

NASA Astrophysics Data System (ADS)

McCammon, J. Andrew

2002-03-01

Proteins have rough energy landscapes. Often more states than just the ground state are occupied and have biological functions. It is essential to study these conformational substates and the dynamical transitions among them. Acetylcholinesterase (AChE) is an important enzyme that has biological functions including the termination of synaptic transmission signals. X-ray structures show that it has an active site that is accessible only via a long and narrow channel from its surface. Therefore the fact that acetylcholine and larger ligands can reach the active site is believed to reflect the protein's structural fluctuation. We carried out long molecular dynamics simulations to investigate the dynamics of AChE and its relation to biological function, and compared our results with experiments. The results reveal several "doors" that open intermittantly between the active site and the surface. Instead of having simple exponential decay correlation functions, the time series of these channels reveal complex, fractal gating between conformations. We also compared the AChE dynamics data with those from an AchE-fasciculin complex. (Fasciculin is a small protein that is a natural inhibitor of AChE.) The results show remarkable effects of the protein-protein interaction, including allosteric and dynamical inhibition by fasciculin besides direct steric blocking. More information and images can be found at http://mccammon.ucsd.edu

A Variable Polyglutamine Repeat Affects Subcellular Localization and Regulatory Activity of a Populus ANGUSTIFOLIA Protein.

PubMed

Bryan, Anthony C; Zhang, Jin; Guo, Jianjun; Ranjan, Priya; Singan, Vasanth; Barry, Kerrie; Schmutz, Jeremy; Weighill, Deborah; Jacobson, Daniel; Jawdy, Sara; Tuskan, Gerald A; Chen, Jin-Gui; Muchero, Wellington

2018-06-08

Polyglutamine (polyQ) stretches have been reported to occur in proteins across many organisms including animals, fungi and plants. Expansion of these repeats has attracted much attention due their associations with numerous human diseases including Huntington's and other neurological maladies. This suggests that the relative length of polyQ stretches is an important modulator of their function. Here, we report the identification of a Populus C-terminus binding protein (CtBP) ANGUSTIFOLIA ( PtAN1 ) which contains a polyQ stretch whose functional relevance had not been established. Analysis of 917 resequenced Populus trichocarpa genotypes revealed three allelic variants at this locus encoding 11-, 13- and 15-glutamine residues. Transient expression assays using Populus leaf mesophyll protoplasts revealed that the 11Q variant exhibited strong nuclear localization whereas the 15Q variant was only found in the cytosol, with the 13Q variant exhibiting localization in both subcellular compartments. We assessed functional implications by evaluating expression changes of putative PtAN1 targets in response to overexpression of the three allelic variants and observed allele-specific differences in expression levels of putative targets. Our results provide evidence that variation in polyQ length modulates PtAN1 function by altering subcellular localization. Copyright © 2018, G3: Genes, Genomes, Genetics.

Functional Roles of Slow Enzyme Conformational Changes in Network Dynamics

PubMed Central

Wu, Zhanghan; Xing, Jianhua

2012-01-01

Extensive studies from different fields reveal that many macromolecules, especially enzymes, show slow transitions among different conformations. This phenomenon is named such things as dynamic disorder, heterogeneity, hysteretic or mnemonic enzymes across these different fields, and has been directly demonstrated by single molecule enzymology and NMR studies recently. We analyzed enzyme slow conformational changes in the context of regulatory networks. A single enzymatic reaction with slow conformational changes can filter upstream network noises, and can either resonantly respond to the system stimulus at certain frequencies or respond adaptively for sustained input signals of the network fluctuations. It thus can serve as a basic functional motif with properties that are normally for larger intermolecular networks in the field of systems biology. We further analyzed examples including enzymes functioning against pH fluctuations, metabolic state change of Artemia embryos, and kinetic insulation of fluctuations in metabolic networks. The study also suggests that hysteretic enzymes may be building blocks of synthetic networks with various properties such as narrow-banded filtering. The work fills the missing gap between studies on enzyme biophysics and network level dynamics, and reveals that the coupling between the two is functionally important; it also suggests that the conformational dynamics of some enzymes may be evolutionally selected. PMID:23009855

Imagine All the People: How the Brain Creates and Uses Personality Models to Predict Behavior

PubMed Central

Hassabis, Demis; Spreng, R. Nathan; Rusu, Andrei A.; Robbins, Clifford A.; Mar, Raymond A.; Schacter, Daniel L.

2014-01-01

The behaviors of other people are often central to envisioning the future. The ability to accurately predict the thoughts and actions of others is essential for successful social interactions, with far-reaching consequences. Despite its importance, little is known about how the brain represents people in order to predict behavior. In this functional magnetic resonance imaging study, participants learned the unique personality of 4 protagonists and imagined how each would behave in different scenarios. The protagonists' personalities were composed of 2 traits: Agreeableness and Extraversion. Which protagonist was being imagined was accurately inferred based solely on activity patterns in the medial prefrontal cortex using multivariate pattern classification, providing novel evidence that brain activity can reveal whom someone is thinking about. Lateral temporal and posterior cingulate cortex discriminated between different degrees of agreeableness and extraversion, respectively. Functional connectivity analysis confirmed that regions associated with trait-processing and individual identities were functionally coupled. Activity during the imagination task, and revealed by functional connectivity, was consistent with the default network. Our results suggest that distinct regions code for personality traits, and that the brain combines these traits to represent individuals. The brain then uses this “personality model” to predict the behavior of others in novel situations. PMID:23463340

[Emerging novel therapeutic strategy for α-dystroglycanopathy by Large].

PubMed

Saito, Fumiaki

2011-11-01

The past decade of researches have revealed mutations of known or putative glycosyltransferases in several types of muscular dystrophy, including Fukuyama-type congenital muscular dystrophy. In these disorders, the function of α-dystroglycan is severely decreased, therefore they are called α-dystroglycanopathy. Recently, putative glycosyltransferase Large was shown to restore the defective function of α-dystroglycan, thus, it is an intriguing idea to apply this effect to the therapy of α-dystroglycanopathy. In the present study, we sought to test this possibility. Using several cultured cell lines, we confirmed that the overexpression of Large results in hyperglycosylation and marked enhancement of the function of α-dystroglycan. For this effect, the whole luminal domain of Large was shown to be necessary using several deletion constructs. We further generated transgenic mice overexpressing Large ubiquitously. In each tissue of the mice, the glycosylation of α-dystroglycan and its laminin binding activity was remarkably increased. Moreover, the morphological analyses on each tissue stained by H-E revealed no significant abnormality in the transgenic mice, suggesting no serious side effects by the overexpression of Large. Taken together, these results indicate that the restoration of the function of α-dystroglycan by Large should be an important molecular target to develop therapeutic strategies for α-dystroglycanopathy.

Reporting Recommended Patch Density from Vehicle Panel Vibration Convergence Studies using both DAF and TBL Fits of the Spatial Correlation Function

NASA Technical Reports Server (NTRS)

Smith, Andrew M.; Davis, Robert Ben; LaVerde, Bruce T.; Jones, Douglas C.; Band, Jonathon L.

2012-01-01

Using the patch method to represent the continuous spatial correlation function of a phased pressure field over a structural surface is an approximation. The approximation approaches the continuous function as patches become smaller. Plotting comparisons of the approximation vs the continuous function may provide insight revealing: (1) For what patch size/density should the approximation be very good? (2) What the approximation looks like when it begins to break down? (3) What the approximation looks like when the patch size is grossly too large. Following these observations with a convergence study using one FEM may allow us to see the importance of patch density. We may develop insights that help us to predict sufficient patch density to provide adequate convergence for the intended purpose frequency range of interest

Linking Resting-State Networks in the Prefrontal Cortex to Executive Function: A Functional Near Infrared Spectroscopy Study.

PubMed

Zhao, Jia; Liu, Jiangang; Jiang, Xin; Zhou, Guifei; Chen, Guowei; Ding, Xiao P; Fu, Genyue; Lee, Kang

2016-01-01

Executive function (EF) plays vital roles in our everyday adaptation to the ever-changing environment. However, limited existing studies have linked EF to the resting-state brain activity. The functional connectivity in the resting state between the sub-regions of the brain can reveal the intrinsic neural mechanisms involved in cognitive processing of EF without disturbance from external stimuli. The present study investigated the relations between the behavioral executive function (EF) scores and the resting-state functional network topological properties in the Prefrontal Cortex (PFC). We constructed complex brain functional networks in the PFC from 90 healthy young adults using functional near infrared spectroscopy (fNIRS). We calculated the correlations between the typical network topological properties (regional topological properties and global topological properties) and the scores of both the Total EF and components of EF measured by computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB). We found that the Total EF scores were positively correlated with regional properties in the right dorsal superior frontal gyrus (SFG), whereas the opposite pattern was found in the right triangular inferior frontal gyrus (IFG). Different EF components were related to different regional properties in various PFC areas, such as planning in the right middle frontal gyrus (MFG), working memory mainly in the right MFG and triangular IFG, short-term memory in the left dorsal SFG, and task switch in the right MFG. In contrast, there were no significant findings for global topological properties. Our findings suggested that the PFC plays an important role in individuals' behavioral performance in the executive function tasks. Further, the resting-state functional network can reveal the intrinsic neural mechanisms involved in behavioral EF abilities.

Using Evolution to Guide Protein Engineering: The Devil IS in the Details.

PubMed

Swint-Kruse, Liskin

2016-07-12

For decades, protein engineers have endeavored to reengineer existing proteins for novel applications. Overall, protein folds and gross functions can be readily transferred from one protein to another by transplanting large blocks of sequence (i.e., domain recombination). However, predictably fine-tuning function (e.g., by adjusting ligand affinity, specificity, catalysis, and/or allosteric regulation) remains a challenge. One approach has been to use the sequences of protein families to identify amino acid positions that change during the evolution of functional variation. The rationale is that these nonconserved positions could be mutated to predictably fine-tune function. Evolutionary approaches to protein design have had some success, but the engineered proteins seldom replicate the functional performances of natural proteins. This Biophysical Perspective reviews several complexities that have been revealed by evolutionary and experimental studies of protein function. These include 1) challenges in defining computational and biological thresholds that define important amino acids; 2) the co-occurrence of many different patterns of amino acid changes in evolutionary data; 3) difficulties in mapping the patterns of amino acid changes to discrete functional parameters; 4) the nonconventional mutational outcomes that occur for a particular group of functionally important, nonconserved positions; 5) epistasis (nonadditivity) among multiple mutations; and 6) the fact that a large fraction of a protein's amino acids contribute to its overall function. To overcome these challenges, new goals are identified for future studies. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

States of curiosity modulate hippocampus-dependent learning via the dopaminergic circuit

PubMed Central

Gruber, Matthias J.; Gelman, Bernard D.; Ranganath, Charan

2014-01-01

Summary People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day delayed memory tests, participants showed improved memory for information that they were curious about, and also for incidental material learned during states of high curiosity. FMRI results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity-driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity in order to create more effective learning experiences. PMID:25284006

Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases?

PubMed

Oppermann, Udo

2013-04-03

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.

Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases?

PubMed Central

2013-01-01

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases. PMID:23566317

Enigma Variations for Peptides and Their Transporters in Higher Plants

PubMed Central

WATERWORTH, WANDA M.; BRAY, CLIFFORD M.

2006-01-01

• Background. Two families of proteins that transport small peptides, the oligopeptide transporters (OPTs) and the peptide transporters (PTRs), have been recognized in eukaryotes. Higher plants contain a far greater number of genes for these transporters than do other eukaryotes. This may be indicative of the relative importance of (oligo)peptides and their transport to plant growth and metabolism. • Recent progress. Recent studies are now allowing us to assign functions to these transporters and are starting to identify their in-planta substrates, revealing unexpected and important contributions of the transporters to plant growth and developmental processes. This Botanical Briefing appraises recent findings that PTRs and OPTs have key roles to play in the control of plant cell growth and development. Evidence is presented that some of these transporters have functions outside that of nitrogen nutrition and that these carriers can also surprise us with their totally unexpected choice of substrates. PMID:16735405

A widespread plant-fungal-bacterial symbiosis promotes plant biodiversity, plant nutrition and seedling recruitment.

PubMed

van der Heijden, Marcel G A; de Bruin, Susanne; Luckerhoff, Ludo; van Logtestijn, Richard S P; Schlaeppi, Klaus

2016-02-01

Highly diverse microbial assemblages colonize plant roots. It is still poorly understood whether different members of this root microbiome act synergistically by supplying different services (for example, different limiting nutrients) to plants and plant communities. In order to test this, we manipulated the presence of two widespread plant root symbionts, arbuscular mycorrhizal fungi and nitrogen-fixing rhizobia bacteria in model grassland communities established in axenic microcosms. Here, we demonstrate that both symbionts complement each other resulting in increased plant diversity, enhanced seedling recruitment and improved nutrient acquisition compared with a single symbiont situation. Legume seedlings obtained up to 15-fold higher productivity if they formed an association with both symbionts, opposed to productivity they reached with only one symbiont. Our results reveal the importance of functional diversity of symbionts and demonstrate that different members of the root microbiome can complement each other in acquiring different limiting nutrients and in driving important ecosystem functions.

Regulation of Stem Cell Aging by Metabolism and Epigenetics.

PubMed

Ren, Ruotong; Ocampo, Alejandro; Liu, Guang-Hui; Izpisua Belmonte, Juan Carlos

2017-09-05

Stem cell aging and exhaustion are considered important drivers of organismal aging. Age-associated declines in stem cell function are characterized by metabolic and epigenetic changes. Understanding the mechanisms underlying these changes will likely reveal novel therapeutic targets for ameliorating age-associated phenotypes and for prolonging human healthspan. Recent studies have shown that metabolism plays an important role in regulating epigenetic modifications and that this regulation dramatically affects the aging process. This review focuses on current knowledge regarding the mechanisms of stem cell aging, and the links between cellular metabolism and epigenetic regulation. In addition, we discuss how these interactions sense and respond to environmental stress in order to maintain stem cell homeostasis, and how environmental stimuli regulate stem cell function. Additionally, we highlight recent advances in the development of therapeutic strategies to rejuvenate dysfunctional aged stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Functional expression of SCL/TAL1 interrupting locus (Stil) protects retinal dopaminergic cells from neurotoxin-induced degeneration.

PubMed

Li, Jingling; Li, Ping; Carr, Aprell; Wang, Xiaokai; DeLaPaz, April; Sun, Lei; Lee, Eric; Tomei, Erika; Li, Lei

2013-01-11

We previously isolated a dominant mutation, night blindness b (nbb), which causes a late onset of retinal dopaminergic cell degeneration in zebrafish. In this study, we cloned the zebrafish nbb locus. Sequencing results revealed that nbb is a homolog of the vertebrate SCL/TAL1 interrupting locus (Stil). The Stil gene has been shown to play important roles in the regulation of vertebrate embryonic neural development and human cancer cell proliferation. In this study, we demonstrate that functional expression of Stil is also required for neural survival. In zebrafish, decreased expression of Stil resulted in increased toxic susceptibility of retinal dopaminergic cells to 6-hydroxydopamine. Increases in Stil-mediated Shh signaling transduction (i.e. by knocking down the Shh repressor Sufu) prevented dopaminergic cell death induced by neurotoxic insult. The data suggest that the oncogene Stil also plays important roles in neural protection.

Pak4 Is Required during Epithelial Polarity Remodeling through Regulating AJ Stability and Bazooka Retention at the ZA

PubMed Central

Walther, Rhian F.; Nunes de Almeida, Francisca; Vlassaks, Evi; Burden, Jemima J.; Pichaud, Franck

2016-01-01

Summary The ability of epithelial cells to assemble into sheets relies on their zonula adherens (ZA), a circumferential belt of adherens junction (AJ) material, which can be remodeled during development to shape organs. Here, we show that during ZA remodeling in a model neuroepithelial cell, the Cdc42 effector P21-activated kinase 4 (Pak4/Mbt) regulates AJ morphogenesis and stability through β-catenin (β-cat/Arm) phosphorylation. We find that β-catenin phosphorylation by Mbt, and associated AJ morphogenesis, is needed for the retention of the apical determinant Par3/Bazooka at the remodeling ZA. Importantly, this retention mechanism functions together with Par1-dependent lateral exclusion of Par3/Bazooka to regulate apical membrane differentiation. Our results reveal an important functional link between Pak4, AJ material morphogenesis, and polarity remodeling during organogenesis downstream of Par3. PMID:27052178

The importance of the function of exercise in the relationship between obligatory exercise and eating and body image concerns.

PubMed

De Young, Kyle P; Anderson, Drew A

2010-01-01

This study tested whether exercising in response to negative affect moderates the association between obligatory exercise and eating and body image psychopathology. Participants (n=226) completed the Eating Disorders Examination-Questionnaire (EDE-Q), Obligatory Exercise Questionnaire (OEQ), and a question assessing whether they ever exercise in response to negative affect. In total, 132 (58.4%) participants endorsed exercising in response to negative affect. Multiple regression analyses revealed significant main effects of negative affect motivated exercise, OEQ total scores, and gender on all four EDE-Q subscales and significant interactions of negative affect motivated exercise and OEQ scores on the Eating Concern, Shape Concern, and Weight Concern scales but not the Restraint scale of the EDE-Q. Obligatory exercisers may not demonstrate elevated eating and body image concerns in the absence of negative affect motivated exercise, providing further support of the importance of the function of exercise.

An epigenetic view of developmental diseases: new targets, new therapies.

PubMed

Xie, Pei; Zang, Li-Qun; Li, Xue-Kun; Shu, Qiang

2016-08-01

Function of epigenetic modifications is one of the most competitive fields in life science. Over the past several decades, it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases. In the present review, we summarize the recent progress about the function of epigenetic regulation, especially DNA and RNA modifications in developmental diseases. Original research articles and literature reviews published in PubMed-indexed journals. DNA modifications including methylation and demethylation can regulate gene expression, and are involved in development and multiple diseases including Rett syndrome, Autism spectrum disorders, congenital heart disease and cancer, etc. RNA methylation and demethylation play important roles in RNA processing, reprogramming, circadian, and neuronal activity, and then modulate development. DNA and RNA modifications play important roles in development and diseases through regulating gene expression. Epigenetic components could serve as novel targets for the treatment of developmental diseases.

Genome-wide analysis of the Glycerol-3-Phosphate Acyltransferase (GPAT) gene family reveals the evolution and diversification of plant GPATs

PubMed Central

Waschburger, Edgar; Kulcheski, Franceli Rodrigues; Veto, Nicole Moreira; Margis, Rogerio; Margis-Pinheiro, Marcia; Turchetto-Zolet, Andreia Carina

2018-01-01

Abstract sn-Glycerol-3-phosphate 1-O-acyltransferase (GPAT) is an important enzyme that catalyzes the transfer of an acyl group from acyl-CoA or acyl-ACP to the sn-1 or sn-2 position of sn-glycerol-3-phosphate (G3P) to generate lysophosphatidic acids (LPAs). The functional studies of GPAT in plants demonstrated its importance in controlling storage and membrane lipid. Identifying genes encoding GPAT in a variety of plant species is crucial to understand their involvement in different metabolic pathways and physiological functions. Here, we performed genome-wide and evolutionary analyses of GPATs in plants. GPAT genes were identified in all algae and plants studied. The phylogenetic analysis showed that these genes group into three main clades. While clades I (GPAT9) and II (soluble GPAT) include GPATs from algae and plants, clade III (GPAT1-8) includes GPATs specific from plants that are involved in the biosynthesis of cutin or suberin. Gene organization and the expression pattern of GPATs in plants corroborate with clade formation in the phylogeny, suggesting that the evolutionary patterns is reflected in their functionality. Overall, our results provide important insights into the evolution of the plant GPATs and allowed us to explore the evolutionary mechanism underlying the functional diversification among these genes. PMID:29583156

The Peroxisomal NAD Carrier from Arabidopsis Imports NAD in Exchange with AMP.

PubMed

van Roermund, Carlo W T; Schroers, Martin G; Wiese, Jan; Facchinelli, Fabio; Kurz, Samantha; Wilkinson, Sabrina; Charton, Lennart; Wanders, Ronald J A; Waterham, Hans R; Weber, Andreas P M; Link, Nicole

2016-07-01

Cofactors such as NAD, AMP, and Coenzyme A (CoA) are essential for a diverse set of reactions and pathways in the cell. Specific carrier proteins are required to distribute these cofactors to different cell compartments, including peroxisomes. We previously identified a peroxisomal transport protein in Arabidopsis (Arabidopsis thaliana) called the peroxisomal NAD carrier (PXN). When assayed in vitro, this carrier exhibits versatile transport functions, e.g. catalyzing the import of NAD or CoA, the exchange of NAD/NADH, and the export of CoA. These observations raise the question about the physiological function of PXN in plants. Here, we used Saccharomyces cerevisiae to address this question. First, we confirmed that PXN, when expressed in yeast, is active and targeted to yeast peroxisomes. Secondl, detailed uptake analyses revealed that the CoA transport function of PXN can be excluded under physiological conditions due to its low affinity for this substrate. Third, we expressed PXN in diverse mutant yeast strains and investigated the suppression of the mutant phenotypes. These studies provided strong evidences that PXN was not able to function as a CoA transporter or a redox shuttle by mediating a NAD/NADH exchange, but instead catalyzed the import of NAD into peroxisomes against AMP in intact yeast cells. © 2016 American Society of Plant Biologists. All Rights Reserved.

Macrophage origin limits functional plasticity in helminth-bacterial co-infection

PubMed Central

Campbell, Sharon M.; Duncan, Sheelagh; Hewitson, James P.; Barr, Tom A.; Jackson-Jones, Lucy H.; Maizels, Rick M.

2017-01-01

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell. PMID:28334040

E3 ubiquitin ligase SP1 regulates peroxisome biogenesis in Arabidopsis

DOE PAGES

Pan, Ronghui; Satkovich, John; Hu, Jianping

2016-10-31

Peroxisomes are ubiquitous eukaryotic organelles that play pivotal roles in a suite of metabolic processes and often act coordinately with other organelles, such as chloroplasts and mitochondria. Peroxisomes import proteins to the peroxisome matrix by peroxins (PEX proteins), but how the function of the PEX proteins is regulated is poorly understood. In this study, we identified the Arabidopsis RING (really interesting new gene) type E3 ubiquitin ligase SP1 [suppressor of plastid protein import locus 1 (ppi1) 1] as a peroxisome membrane protein with a regulatory role in peroxisome protein import. SP1 interacts physically with the two components of the peroxisomemore » protein docking complex PEX13–PEX14 and the (RING)-finger peroxin PEX2. Loss of SP1 function suppresses defects of the pex14-2 and pex13-1 mutants, and SP1 is involved in the degradation of PEX13 and possibly PEX14 and all three RING peroxins. An in vivo ubiquitination assay showed that SP1 has the ability to promote PEX13 ubiquitination. Our study has revealed that, in addition to its previously reported function in chloroplast biogenesis, SP1 plays a role in peroxisome biogenesis. The same E3 ubiquitin ligase promotes the destabilization of components of two distinct protein-import machineries, indicating that degradation of organelle biogenesis factors by the ubiquitin–proteasome system may constitute an important regulatory mechanism in coordinating the biogenesis of metabolically linked organelles in eukaryotes.« less

Hypnotic Approaches for Chronic Pain Management

PubMed Central

Jensen, Mark P.; Patterson, David R.

2015-01-01

The empirical support for hypnosis for chronic pain management has flourished over the past two decades. Clinical trials show that hypnosis is effective for reducing chronic pain, although outcomes vary between individuals. The findings from these clinical trials also show that hypnotic treatments have a number of positive effects beyond pain control. Neurophysiological studies reveal that hypnotic analgesia has clear effects on brain and spinal-cord functioning that differ as a function of the specific hypnotic suggestions made, providing further evidence for the specific effects of hypnosis. The research results have important implications for how clinicians can help their clients experience maximum benefits from hypnosis and treatments that include hypnotic components. PMID:24547802

Illuminating Neural Circuits: From Molecules to MRI.

PubMed

Lee, Jin Hyung; Kreitzer, Anatol C; Singer, Annabelle C; Schiff, Nicholas D

2017-11-08

Neurological disease drives symptoms through pathological changes to circuit functions. Therefore, understanding circuit mechanisms that drive behavioral dysfunction is of critical importance for quantitative diagnosis and systematic treatment of neurological disease. Here, we describe key technologies that enable measurement and manipulation of neural activity and neural circuits. Applying these approaches led to the discovery of circuit mechanisms underlying pathological motor behavior, arousal regulation, and protein accumulation. Finally, we discuss how optogenetic functional magnetic resonance imaging reveals global scale circuit mechanisms, and how circuit manipulations could lead to new treatments of neurological diseases. Copyright © 2017 the authors 0270-6474/17/3710817-09$15.00/0.

Emotion unfolded by motion: a role for parietal lobe in decoding dynamic facial expressions.

PubMed

Sarkheil, Pegah; Goebel, Rainer; Schneider, Frank; Mathiak, Klaus

2013-12-01

Facial expressions convey important emotional and social information and are frequently applied in investigations of human affective processing. Dynamic faces may provide higher ecological validity to examine perceptual and cognitive processing of facial expressions. Higher order processing of emotional faces was addressed by varying the task and virtual face models systematically. Blood oxygenation level-dependent activation was assessed using functional magnetic resonance imaging in 20 healthy volunteers while viewing and evaluating either emotion or gender intensity of dynamic face stimuli. A general linear model analysis revealed that high valence activated a network of motion-responsive areas, indicating that visual motion areas support perceptual coding for the motion-based intensity of facial expressions. The comparison of emotion with gender discrimination task revealed increased activation of inferior parietal lobule, which highlights the involvement of parietal areas in processing of high level features of faces. Dynamic emotional stimuli may help to emphasize functions of the hypothesized 'extended' over the 'core' system for face processing.

Trophic segregation of a fish assemblage along lateral depth gradients in a subtropical coastal lagoon revealed by stable isotope analyses.

PubMed

Mont'Alverne, R; Pereyra, P E R; Garcia, A M

2016-07-01

Stable isotopes were used to evaluate the hypothesis that fish assemblages occurring in shallow and deep areas of a large coastal lagoon are structured in partially segregated trophic modules with consumers showing contrasting reliance on benthic or pelagic food sources. The results revealed that fishes in deep areas were mainly dependent on particulate organic matter in the sediment (SOM), whereas emergent macrophytes were as important as SOM to fish consumers in shallow areas. Conceptual trophic diagrams depicting relationships among basal food sources and consumers in different regions of the lagoon highlighted the greater use of multiple basal food sources by more feeding mode functional guilds in shallow water compared with the use of predominantly benthic resources (SOM) in deep areas. The findings appear to corroborate the initial hypothesis and offer complementary perspectives in understanding the role of spatial ecology in structuring coastal ecosystem function and productivity. © 2016 The Fisheries Society of the British Isles.

Cell and region specificity of Aryl hydrocarbon Receptor (AhR) system in the testis and the epididymis.

PubMed

Wajda, A; Łapczuk, J; Grabowska, M; Pius-Sadowska, E; Słojewski, M; Laszczynska, M; Urasinska, E; Machalinski, B; Drozdzik, M

2017-04-01

Aryl hydrocarbon receptor (AhR) plays multiple important functions in adaptive responses. Exposure to AhR ligands may produce an altered metabolic activity controlled by the AhR pathways, and consequently affect drug/toxin responses, hormonal status and cellular homeostasis. This research revealed species-, cell- and region-specific pattern of the AhR system expression in the rat and human testis and epididymis, complementing the existing knowledge, especially within the epididymal segments. The study showed that AhR level in the rat and human epididymis is higher than in the testis. The downregulation of AhR expression after TCDD treatment was revealed in the spermatogenic cells at different stages and the epididymal epithelial cells, but not in the Sertoli and Leydig cells. Hence, this basic research provides information about the AhR function in the testis and epididymis, which may provide an insight into deleterious effects of drugs, hormones and environmental pollutants on male fertility. Copyright © 2017 Elsevier Inc. All rights reserved.

[Three-dimensional genome organization: a lesson from the Polycomb-Group proteins].

PubMed

Bantignies, Frédéric

2013-01-01

As more and more genomes are being explored and annotated, important features of three-dimensional (3D) genome organization are just being uncovered. In the light of what we know about Polycomb group (PcG) proteins, we will present the latest findings on this topic. The PcG proteins are well-conserved chromatin factors that repress transcription of numerous target genes. They bind the genome at specific sites, forming chromatin domains of associated histone modifications as well as higher-order chromatin structures. These 3D chromatin structures involve the interactions between PcG-bound regulatory regions at short- and long-range distances, and may significantly contribute to PcG function. Recent high throughput "Chromosome Conformation Capture" (3C) analyses have revealed many other higher order structures along the chromatin fiber, partitioning the genomes into well demarcated topological domains. This revealed an unprecedented link between linear epigenetic domains and chromosome architecture, which might be intimately connected to genome function. © Société de Biologie, 2013.

Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

PubMed

Lilja, Anna M; Rodilla, Veronica; Huyghe, Mathilde; Hannezo, Edouard; Landragin, Camille; Renaud, Olivier; Leroy, Olivier; Rulands, Steffen; Simons, Benjamin D; Fre, Silvia

2018-06-01

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.

Density Functional Theory Study of Spirodienone Stereoisomers in Lignin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elder, Thomas; Berstis, Laura; Beckham, Gregg T.

The spirodienone structure in lignin is a relatively recent discovery, and it has been found to occur in lignin of various plant species at concentrations of ~3%, which is sufficiently high to be important for better understanding of its properties and reactivity. The cyclic structure, with a ..beta..-1 bond, has been proposed to be a precursor for acyclic ..beta..-1 linkages in lignin. Previous analytical work has revealed the presence, but not the absolute configuration, of two stereoisomeric forms of spirodienone. The objective of the current work was to determine if there are thermodynamic differences that could help identify the experimentallymore » observed stereoisomers. Results from density functional theory calculations reveal the presence of clusters of stereoisomers with varying stability that may be of use in narrowing the list of possible structures. Furthermore, the bond dissociation enthalpy of the cyclic ring exhibited a particularly high value for the C-O cleavage reaction relative to more conventional ether bonds in lignin, perhaps due to limited electron delocalization possibilities.« less

Density Functional Theory Study of Spirodienone Stereoisomers in Lignin

DOE PAGES

Elder, Thomas; Berstis, Laura; Beckham, Gregg T.; ...

2017-06-28

The spirodienone structure in lignin is a relatively recent discovery, and it has been found to occur in lignin of various plant species at concentrations of ~3%, which is sufficiently high to be important for better understanding of its properties and reactivity. The cyclic structure, with a ..beta..-1 bond, has been proposed to be a precursor for acyclic ..beta..-1 linkages in lignin. Previous analytical work has revealed the presence, but not the absolute configuration, of two stereoisomeric forms of spirodienone. The objective of the current work was to determine if there are thermodynamic differences that could help identify the experimentallymore » observed stereoisomers. Results from density functional theory calculations reveal the presence of clusters of stereoisomers with varying stability that may be of use in narrowing the list of possible structures. Furthermore, the bond dissociation enthalpy of the cyclic ring exhibited a particularly high value for the C-O cleavage reaction relative to more conventional ether bonds in lignin, perhaps due to limited electron delocalization possibilities.« less

Impaired limb reaction to displacement of center of gravity in rats with unilateral striatal ischemic injury.

PubMed

Nobile, Cameron W; Palmateer, Julie M; Kane, Jackie; Hurn, Patricia D; Schallert, Timothy; Adkins, DeAnna L

2014-10-01

Clinical stroke often results in impaired balance and increased vulnerability to severe injuries due to falling. To evaluate potential preclinical treatments that might target these deficits, it will be important to include tests capable of assessing these impairments chronically in animal models. Previously, we developed a postural instability test (PIT) that revealed chronic, unilateral impairments in postural stability in rat models of hemi-Parkinson's disease (PD) and of unilateral cervical spinal cord injury. Here, we investigated whether this test was also capable of revealing long-term stroke-induced impairments in postural support in rats. Additionally, we examined the ability of more common tests of sensorimotor function to detect chronic impairments. We found that the PIT detected chronic deficits in postural stability/balance enduring for up to 6 weeks post-stroke, outlasting impairments detected in other tests of forelimb sensorimotor function, including asymmetries in upright postural support (cylinder test) and vibrissae-evoked forelimb placing.

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development.

PubMed

Li, Jun; Han, Wenyan; Pelkey, Kenneth A; Duan, Jingjing; Mao, Xia; Wang, Ya-Xian; Craig, Michael T; Dong, Lijin; Petralia, Ronald S; McBain, Chris J; Lu, Wei

2017-11-15

In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development. Published by Elsevier Inc.

Asymmetric activation mechanism of a homodimeric red light regulated photoreceptor.

PubMed

Gourinchas, Geoffrey; Heintz, Udo; Winkler, Andreas

2018-06-05

Organisms adapt to environmental cues using diverse signaling networks. In order to sense and integrate light for regulating various biological functions, photoreceptor proteins have evolved in a modular way. This modularity is targeted in the development of optogenetic tools enabling the control of cellular events with high spatiotemporal precision. However, the limited understanding of signaling mechanisms impedes the rational design of innovative photoreceptor-effector couples. Here we reveal molecular details of signal transduction in phytochrome-regulated diguanylyl-cyclases. Asymmetric structural changes of the full-length homodimer result in a functional heterodimer featuring two different photoactivation states. Structural changes around the cofactors result in a quasi-translational rearrangement of the distant coiled-coil sensor-effector linker. Eventually, this regulates enzymatic activity by modulating the dimer interface of the output domains. Considering the importance of phytochrome heterodimerization in plant signaling, our mechanistic details of asymmetric photoactivation in a bacterial system reveal novel aspects of the evolutionary adaptation of phytochromes. © 2018, Gourinchas et al.

Characterization of vacuolar amino acid transporter from Fusarium oxysporum in Saccharomyces cerevisiae.

PubMed

Lunprom, Siriporn; Pongcharoen, Pongsanat; Sekito, Takayuki; Kawano-Kawada, Miyuki; Kakinuma, Yoshimi; Akiyama, Koichi

2015-01-01

Fusarium oxysporum causes wilt disease in many plant families, and many genes are involved in its development or growth in host plants. A recent study revealed that vacuolar amino acid transporters play an important role in spore formation in Schizosaccharomyces pombe and Saccharomyces cerevisiae. To investigate the role of vacuolar amino acid transporters of this phytopathogenic fungus, the FOXG_11334 (FoAVT3) gene from F. oxysporum was isolated and its function was characterized. Transcription of FoAVT3 was upregulated after rapamycin treatment. A green fluorescent protein fusion of FoAvt3p was localized to vacuolar membranes in both S. cerevisiae and F. oxysporum. Analysis of the amino acid content of the vacuolar fraction and amino acid transport activities using vacuolar membrane vesicles from S. cerevisiae cells heterologously expressing FoAVT3 revealed that FoAvt3p functions as a vacuolar amino acid transporter, exporting neutral amino acids. We conclude that the FoAVT3 gene encodes a vacuolar neutral amino acid transporter.

The Structure of the GM-CSF Receptor Complex Reveals a Distinct Mode of Cytokine Receptor Activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hansen, Guido; Hercus, Timothy R.; McClure, Barbara J.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in clinical conditions such as rheumatoid arthritis and leukemia, yet offers therapeutic value for other diseases. Its receptors are heterodimers consisting of a ligand-specific {alpha} subunit and a {beta}c subunit that is shared with the interleukin (IL)-3 and IL-5 receptors. How signaling is initiated remains an enigma. We report here the crystal structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into an unexpected dodecamer or higher-order complex. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface andmore » functional studies reveal that dodecamer formation is required for receptor activation and signaling. This unusual form of receptor assembly likely applies also to IL-3 and IL-5 receptors, providing a structural basis for understanding their mechanism of activation and for the development of therapeutics.« less

Three Types of Cortical L5 Neurons that Differ in Brain-Wide Connectivity and Function

PubMed Central

Kim, Euiseok J.; Juavinett, Ashley L.; Kyubwa, Espoir M.; Jacobs, Matthew W.; Callaway, Edward M.

2015-01-01

SUMMARY Cortical layer 5 (L5) pyramidal neurons integrate inputs from many sources and distribute outputs to cortical and subcortical structures. Previous studies demonstrate two L5 pyramid types: cortico-cortical (CC) and cortico-subcortical (CS). We characterize connectivity and function of these cell types in mouse primary visual cortex and reveal a new subtype. Unlike previously described L5 CC and CS neurons, this new subtype does not project to striatum [cortico-cortical, non-striatal (CC-NS)] and has distinct morphology, physiology and visual responses. Monosynaptic rabies tracing reveals that CC neurons preferentially receive input from higher visual areas, while CS neurons receive more input from structures implicated in top-down modulation of brain states. CS neurons are also more direction-selective and prefer faster stimuli than CC neurons. These differences suggest distinct roles as specialized output channels, with CS neurons integrating information and generating responses more relevant to movement control and CC neurons being more important in visual perception. PMID:26671462

Three Types of Cortical Layer 5 Neurons That Differ in Brain-wide Connectivity and Function.

PubMed

Kim, Euiseok J; Juavinett, Ashley L; Kyubwa, Espoir M; Jacobs, Matthew W; Callaway, Edward M

2015-12-16

Cortical layer 5 (L5) pyramidal neurons integrate inputs from many sources and distribute outputs to cortical and subcortical structures. Previous studies demonstrate two L5 pyramid types: cortico-cortical (CC) and cortico-subcortical (CS). We characterize connectivity and function of these cell types in mouse primary visual cortex and reveal a new subtype. Unlike previously described L5 CC and CS neurons, this new subtype does not project to striatum [cortico-cortical, non-striatal (CC-NS)] and has distinct morphology, physiology, and visual responses. Monosynaptic rabies tracing reveals that CC neurons preferentially receive input from higher visual areas, while CS neurons receive more input from structures implicated in top-down modulation of brain states. CS neurons are also more direction-selective and prefer faster stimuli than CC neurons. These differences suggest distinct roles as specialized output channels, with CS neurons integrating information and generating responses more relevant to movement control and CC neurons being more important in visual perception. Copyright © 2015 Elsevier Inc. All rights reserved.

Structural Determination of Functional Domains in Early B-cell Factor (EBF) Family of Transcription Factors Reveals Similarities to Rel DNA-binding Proteins and a Novel Dimerization Motif*

PubMed Central

Siponen, Marina I.; Wisniewska, Magdalena; Lehtiö, Lari; Johansson, Ida; Svensson, Linda; Raszewski, Grzegorz; Nilsson, Lennart; Sigvardsson, Mikael; Berglund, Helena

2010-01-01

The early B-cell factor (EBF) transcription factors are central regulators of development in several organs and tissues. This protein family shows low sequence similarity to other protein families, which is why structural information for the functional domains of these proteins is crucial to understand their biochemical features. We have used a modular approach to determine the crystal structures of the structured domains in the EBF family. The DNA binding domain reveals a striking resemblance to the DNA binding domains of the Rel homology superfamily of transcription factors but contains a unique zinc binding structure, termed zinc knuckle. Further the EBF proteins contain an IPT/TIG domain and an atypical helix-loop-helix domain with a novel type of dimerization motif. The data presented here provide insights into unique structural features of the EBF proteins and open possibilities for detailed molecular investigations of this important transcription factor family. PMID:20592035

Effect of polybrominated diphenyl ether (PBDE) treatment on the composition and function of the bacterial community in the sponge Haliclona cymaeformis

PubMed Central

Tian, Ren-Mao; Lee, On On; Wang, Yong; Cai, Lin; Bougouffa, Salim; Chiu, Jill Man Ying; Wu, Rudolf Shiu Sun; Qian, Pei-Yuan

2014-01-01

Marine sponges play important roles in benthic environments and are sensitive to environmental stresses. Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants since the 1970s and are cytotoxic and genotoxic to organisms. In the present study, we studied the short-period effect of PBDE-47 (2,2′,4,4′-tetrabromodiphenyl ether) treatment on the community structure and functional gene composition of the bacterial community inhabiting the marine sponge Haliclona cymaeformis. Our results showed that the bacterial community shifted from an autotrophic bacteria-dominated community to a heterotrophic bacteria-dominated community in response to PBDE-47 in a time- and concentration-dependent manner. A potentially symbiotic sulfur-oxidizing bacterium (SOB) was dominant (>80% in abundance) in the untreated sponge. However, exposure to a high concentration (1 μg/L) of PBDE-47 caused a substantial decrease in the potential symbiont and an enrichment of heterotrophic bacteria like Clostridium. A metagenomic analysis showed a selective effect of the high concentration treatment on the functional gene composition of the enriched heterotrophic bacteria, revealing an enrichment for the functions responsible for DNA repair, multidrug efflux pumping, and bacterial chemotaxis and motility. This study demonstrated that PBDE-47 induced a shift in the composition of the community and functional genes in the sponge-associated bacterial community, revealing the selective effect of PBDE-47 treatment on the functions of the bacterial community in the microenvironment of the sponge. PMID:25642227

Microbial functional diversity plays an important role in the degradation of polyhydroxybutyrate (PHB) in soil.

PubMed

Dey, Samrat; Tribedi, Prosun

2018-03-01

Towards bioremediation of recalcitrant materials like synthetic polymer, soil has been recognized as a traditional site for disposal and subsequent degradation as some microorganisms in soil can degrade the polymer in a non-toxic, cost-effective, and environment friendly way. Microbial functional diversity is a constituent of biodiversity that includes wide range of metabolic activities that can influence numerous aspects of ecosystem functioning like ecosystem stability, nutrient availability, ecosystem dynamics, etc. Thus, in the current study, we assumed that microbial functional diversity could play an important role in polymer degradation in soil. To verify this hypothesis, we isolated soil from five different sites of landfill and examined several microbiological parameters wherein we observed a significant variation in heterotrophic microbial count as well as microbial activities among the soil microcosms tested. Multivariate analysis (principle component analysis) based on the carbon sources utilization pattern revealed that soil microcosms showed different metabolic patterns suggesting the variable distribution of microorganisms among the soil microcosms tested. Since microbial functional diversity depends on both microbial richness and evenness, Shannon diversity index was determined to measure microbial richness and Gini coefficient was determined to measure microbial evenness. The tested soil microcosms exhibited variation in both microbial richness and evenness suggesting the considerable difference in microbial functional diversity among the tested microcosms. We then measured polyhydroxybutyrate (PHB) degradation in soil microcosms after desired period of incubation of PHB in soil wherein we found that soil microcosms having higher functional diversity showed enhanced PHB degradation and soil microcosms having lower functional diversity showed reduced PHB degradation. We also noticed that all the tested soil microcosms showed similar pattern in both microbial functional diversity and PHB degradation suggesting a strong positive correlation ( r  = 0.95) between microbial functional diversity and PHB degradation. Thus, the results demonstrate that microbial functional diversity plays an important role in PHB degradation in soil by exhibiting versatile microbial metabolic potentials that lead to the enhanced degradation of PHB.

X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes.

DTIC Science & Technology

1999-10-01

nerve gas intoxication, as well as of insecticide poisoning. Such structures can yield direct information concerning the functional groups and steric...Glyll7His mutant (48). Recent solution of the 3D structures of conjugates of the nerve agents , sarin, soman, DFP and VX with 7cAChE (49, 50) has revealed... pesticides and chemical warfare agents is a topic of considerable environmental and toxicological importance. Hence, a substantial research effort is being

Endoreplication and polyploidy: insights into development and disease

PubMed Central

Fox, Donald T.; Duronio, Robert J.

2013-01-01

Polyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer. PMID:23222436

Ligation site in proteins recognized in silico

PubMed Central

Brylinski, Michal; Konieczny, Leszek; Roterman, Irena

2006-01-01

Recognition of a ligation site in a protein molecule is important for identifying its biological activity. The model for in silico recognition of ligation sites in proteins is presented. The idealized hydrophobic core stabilizing protein structure is represented by a three-dimensional Gaussian function. The experimentally observed distribution of hydrophobicity compared with the theoretical distribution reveals differences. The area of high differences indicates the ligation site. Availability http://bioinformatics.cm-uj.krakow.pl/activesite PMID:17597871

Guidelines for the Planning of Rural Areas in Europe. A Contribution to an Overall European Regional Planning Policy. Conference Report Presented by the Belgian and German Delegations.

ERIC Educational Resources Information Center

Council of Europe, Strasbourg (France).

Rural regional planning that will satisfy man's real needs, and not merely those of an economic nature, must take into consideration all factors, all possible interactions, and most important of all, those values which cannot be expressed in terms of money. The report details the functions and problems of rural areas revealed by analyses of rural…

Analysis of Glu-1 deletion lines reveals the importance of high molecular weight glutenin subunits 7+9 Glu-B1 in wheat flour tortilla making

USDA-ARS?s Scientific Manuscript database

High molecular weight glutenin subunits (HMW-GS) play a significant role in the functional properties of wheat flour. Wheat lines in which one or more of the HMW-GS alleles were absent from Glu-A1, Glu-B1 or Glu-D1 loci (deletion lines) were compared with non-deletion lines for dough and tortilla ma...

The cell wall hydrolase Pmp23 is important for assembly and stability of the division ring in Streptococcus pneumoniae.

PubMed

Jacq, Maxime; Arthaud, Christopher; Manuse, Sylvie; Mercy, Chryslène; Bellard, Laure; Peters, Katharina; Gallet, Benoit; Galindo, Jennifer; Doan, Thierry; Vollmer, Waldemar; Brun, Yves V; VanNieuwenhze, Michael S; Di Guilmi, Anne Marie; Vernet, Thierry; Grangeasse, Christophe; Morlot, Cecile

2018-05-15

Bacterial division is intimately linked to synthesis and remodeling of the peptidoglycan, a cage-like polymer that surrounds the bacterial cell, providing shape and mechanical resistance. The bacterial division machinery, which is scaffolded by the cytoskeleton protein FtsZ, includes proteins with enzymatic, structural or regulatory functions. These proteins establish a complex network of transient functional and/or physical interactions which preserve cell shape and cell integrity. Cell wall hydrolases required for peptidoglycan remodeling are major contributors to this mechanism. Consistent with this, their deletion or depletion often results in morphological and/or division defects. However, the exact function of most of them remains elusive. In this work, we show that the putative lysozyme activity of the cell wall hydrolase Pmp23 is important for proper morphology and cell division in the opportunistic human pathogen Streptococcus pneumoniae. Our data indicate that active Pmp23 is required for proper localization of the Z-ring and the FtsZ-positioning protein MapZ. In addition, Pmp23 localizes to the division site and interacts directly with the essential peptidoglycan synthase PBP2x. Altogether, our data reveal a new regulatory function for peptidoglycan hydrolases.

Effect of dietary antioxidant supplementation (Cuminum cyminum) on bacterial susceptibility of diabetes-induced rats.

PubMed

Moubarz, Gehan; Embaby, Mohamed A; Doleib, Nada M; Taha, Mona M

2016-01-01

Diabetic patients are at risk of acquiring infections. Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Diabetes causes generation of reactive oxygen species that increases oxidative stress, which may play a role in the development of complications as immune-deficiency and bacterial infection. The study aimed to investigate the role of a natural antioxidant, cumin, in the improvement of immune functions in diabetes. Diabetes was achieved by interperitoneal injection of streptozotocin (STZ). Bacterial infection was induced by application of Staphylococcus aureus suspension to a wound in the back of rats. The antioxidant was administered for 6 weeks. Results revealed a decrease in blood glucose levels in diabetic rats (p < 0.001), in addition to improving immune functions by decreasing total IgE approaching to the normal control level. Also, inflammatory cytokine (IL-6, IL-1β and TNF) levels, as well as total blood count decreased in diabetic rats as compared to the control group. Thus, cumin may serve as anti-diabetic treatment and may help in attenuating diabetic complications by improving immune functions. Therefore, a medical dietary antioxidant supplementation is important to improve the immune functions in diabetes.

Effect of dietary antioxidant supplementation (Cuminum cyminum) on bacterial susceptibility of diabetes-induced rats

PubMed Central

Embaby, Mohamed A.; Doleib, Nada M.; Taha, Mona M.

2016-01-01

Diabetic patients are at risk of acquiring infections. Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Diabetes causes generation of reactive oxygen species that increases oxidative stress, which may play a role in the development of complications as immune-deficiency and bacterial infection. The study aimed to investigate the role of a natural antioxidant, cumin, in the improvement of immune functions in diabetes. Diabetes was achieved by interperitoneal injection of streptozotocin (STZ). Bacterial infection was induced by application of Staphylococcus aureus suspension to a wound in the back of rats. The antioxidant was administered for 6 weeks. Results revealed a decrease in blood glucose levels in diabetic rats (p < 0.001), in addition to improving immune functions by decreasing total IgE approaching to the normal control level. Also, inflammatory cytokine (IL-6, IL-1β and TNF) levels, as well as total blood count decreased in diabetic rats as compared to the control group. Thus, cumin may serve as anti-diabetic treatment and may help in attenuating diabetic complications by improving immune functions. Therefore, a medical dietary antioxidant supplementation is important to improve the immune functions in diabetes. PMID:27536197

Identification and functional analysis of two alternatively spliced transcripts of ABSCISIC ACID INSENSITIVE3 (ABI3) in linseed flax (Linum usitatissimum L.).

PubMed

Wang, Yanyan; Zhang, Tianbao; Song, Xiaxia; Zhang, Jianping; Dang, Zhanhai; Pei, Xinwu; Long, Yan

2018-01-01

Alternative splicing is a popular phenomenon in different types of plants. It can produce alternative spliced transcripts that encode proteins with altered functions. Previous studies have shown that one transcription factor, ABSCISIC ACID INSENSITIVE3 (ABI3), which encodes an important component in abscisic acid (ABA) signaling, is subjected to alternative splicing in both mono- and dicotyledons. In the current study, we identified two homologs of ABI3 in the genome of linseed flax. We screened two alternatively spliced flax LuABI3 transcripts, LuABI3-2 and LuABI3-3, and one normal flax LuABI3 transcript, LuABI3-1. Sequence analysis revealed that one of the alternatively spliced transcripts, LuABI3-3, retained a 6 bp intron. RNA accumulation analysis showed that all three transcripts were expressed during seed development, while subcellular localization and transgene experiments showed that LuABI3-3 had no biological function. The two normal transcripts, LuABI3-1 and LuABI3-2, are the important functional isoforms in flax and play significant roles in the ABA regulatory pathway during seed development, germination, and maturation.

Conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for LANA in chronic MHV68 infection

PubMed Central

Salinas, Eduardo; Sifford, Jeffrey M.; Oldenburg, Darby G.

2018-01-01

Gammaherpesvirus (GHV) pathogenesis is a complex process that involves productive viral replication, dissemination to tissues that harbor lifelong latent infection, and reactivation from latency back into a productive replication cycle. Traditional loss-of-function mutagenesis approaches in mice using murine gammaherpesvirus 68 (MHV68), a model that allows for examination of GHV pathogenesis in vivo, have been invaluable for defining requirements for specific viral gene products in GHV infection. But these approaches are insufficient to fully reveal how viral gene products contribute when the encoded protein facilitates multiple processes in the infectious cycle and when these functions vary over time and from one host tissue to another. To address this complexity, we developed an MHV68 genetic platform that enables cell-type-specific and inducible viral gene deletion in vivo. We employed this system to re-evaluate functions of the MHV68 latency-associated nuclear antigen (mLANA), a protein with roles in both viral replication and latency. Cre-mediated deletion in mice of loxP-flanked ORF73 demonstrated the necessity of mLANA in B cells for MHV68 latency establishment. Impaired latency during the transition from draining lymph nodes to blood following mLANA deletion also was observed, supporting the hypothesis that B cells are a major conduit for viral dissemination. Ablation of mLANA in infected germinal center (GC) B cells severely impaired viral latency, indicating the importance of viral passage through the GC for latency establishment. Finally, induced ablation of mLANA during latency resulted in complete loss of affected viral genomes, indicating that mLANA is critically important for maintenance of viral genomes during stable latency. Collectively, these experiments provide new insights into LANA homolog functions in GHV colonization of the host and highlight the potential of a new MHV68 genetic platform to foster a more complete understanding of viral gene functions at discrete stages of GHV pathogenesis. PMID:29364981

Effects of water flow regulation on ecosystem functioning in a Mediterranean river network assessed by wood decomposition.

PubMed

Abril, Meritxell; Muñoz, Isabel; Casas-Ruiz, Joan P; Gómez-Gener, Lluís; Barceló, Milagros; Oliva, Francesc; Menéndez, Margarita

2015-06-01

Mediterranean rivers are extensively modified by flow regulation practises along their courses. An important part of the river impoundment in this area is related to the presence of small dams constructed mainly for water abstraction purposes. These projects drastically modified the ecosystem morphology, transforming lotic into lentic reaches and increasing their alternation along the river. Hydro-morphologial differences between these reaches indicate that flow regulation can trigger important changes in the ecosystem functioning. Decomposition of organic matter is an integrative process and this complexity makes it a good indicator of changes in the ecosystem. The aim of this study was to assess the effect caused by flow regulation on ecosystem functioning at the river network scale, using wood decomposition as a functional indicator. We studied the mass loss from wood sticks during three months in different lotic and lentic reaches located along a Mediterranean river basin, in both winter and summer. Additionally, we identified the environmental factors affecting decomposition rates along the river orders. The results revealed differences in decomposition rates between sites in both seasons that were principally related to the differences between stream orders. The rates were mainly related to temperature, nutrient concentrations (NO2(-), NO3(2-)) and water residence time. High-order streams with higher temperature and nutrient concentrations exhibited higher decomposition rates compared with low-order streams. The effect of the flow regulation on the decomposition rates only appeared to be significant in high orders, especially in winter, when the hydrological characteristics of lotic and lentic habitats widely varied. Lotic reaches with lower water residence time exhibited greater decomposition rates compared with lentic reaches probably due to more physical abrasion and differences in the microbial assemblages. Overall, our study revealed that in high orders the reduction of flow caused by flow regulation affects the wood decomposition indicating changes in ecosystem functioning. Copyright © 2015 Elsevier B.V. All rights reserved.

The valine and lysine residues in the conserved FxVTxK motif are important for the function of phylogenetically distant plant cellulose synthases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slabaugh, Erin; Scavuzzo-Duggan, Tess; Chaves, Arielle

2015-12-08

Cellulose synthases (CESAs) synthesize the β-1,4-glucan chains that coalesce to form cellulose microfibrils in plant cell walls. In addition to a large cytosolic (catalytic) domain, CESAs have eight predicted transmembrane helices (TMHs). However, analogous to the structure of BcsA, a bacterial CESA, predicted TMH5 in CESA may instead be an interfacial helix. This would place the conserved FxVTxK motif in the plant cell cytosol where it could function as a substrate-gating loop as occurs in BcsA. To define the functional importance of the CESA region containing FxVTxK, we tested five parallel mutations in Arabidopsis thaliana CESA1 and Physcomitrella patens CESA5more » in complementation assays of the relevant cesa mutants. In both organisms, the substitution of the valine or lysine residues in FxVTxK severely affected CESA function. In Arabidopsis roots, both changes were correlated with lower cellulose anisotropy, as revealed by Pontamine Fast Scarlet. Analysis of hypocotyl inner cell wall layers by atomic force microscopy showed that two altered versions of Atcesa1 could rescue cell wall phenotypes observed in the mutant background line. Overall, the data show that the FxVTxK motif is functionally important in two phylogenetically distant plant CESAs. The results show that Physcomitrella provides an efficient model for assessing the effects of engineered CESA mutations affecting primary cell wall synthesis and that diverse testing systems can lead to nuanced insights into CESA structure–function relationships. Although CESA membrane topology needs to be experimentally determined, the results support the possibility that the FxVTxK region functions similarly in CESA and BcsA.« less

Arabidopsis leucine-rich repeat extensin (LRX) proteins modify cell wall composition and influence plant growth.

PubMed

Draeger, Christian; Ndinyanka Fabrice, Tohnyui; Gineau, Emilie; Mouille, Grégory; Kuhn, Benjamin M; Moller, Isabel; Abdou, Marie-Therese; Frey, Beat; Pauly, Markus; Bacic, Antony; Ringli, Christoph

2015-06-24

Leucine-rich repeat extensins (LRXs) are extracellular proteins consisting of an N-terminal leucine-rich repeat (LRR) domain and a C-terminal extensin domain containing the typical features of this class of structural hydroxyproline-rich glycoproteins (HRGPs). The LRR domain is likely to bind an interaction partner, whereas the extensin domain has an anchoring function to insolubilize the protein in the cell wall. Based on the analysis of the root hair-expressed LRX1 and LRX2 of Arabidopsis thaliana, LRX proteins are important for cell wall development. The importance of LRX proteins in non-root hair cells and on the structural changes induced by mutations in LRX genes remains elusive. The LRX gene family of Arabidopsis consists of eleven members, of which LRX3, LRX4, and LRX5 are expressed in aerial organs, such as leaves and stem. The importance of these LRX genes for plant development and particularly cell wall formation was investigated. Synergistic effects of mutations with gradually more severe growth retardation phenotypes in double and triple mutants suggest a similar function of the three genes. Analysis of cell wall composition revealed a number of changes to cell wall polysaccharides in the mutants. LRX3, LRX4, and LRX5, and most likely LRX proteins in general, are important for cell wall development. Due to the complexity of changes in cell wall structures in the lrx mutants, the exact function of LRX proteins remains to be determined. The increasingly strong growth-defect phenotypes in double and triple mutants suggests that the LRX proteins have similar functions and that they are important for proper plant development.

Mitochondrial thiol oxidase Erv1: both shuttle cysteine residues are required for its function with distinct roles

PubMed Central

Ang, Swee Kim; Zhang, Mengqi; Lodi, Tiziana; Lu, Hui

2014-01-01

Erv1 (essential for respiration and viability 1), is an essential component of the MIA (mitochondrial import and assembly) pathway, playing an important role in the oxidative folding of mitochondrial intermembrane space proteins. In the MIA pathway, Mia40, a thiol oxidoreductase with a CPC motif at its active site, oxidizes newly imported substrate proteins. Erv1 a FAD-dependent thiol oxidase, in turn reoxidizes Mia40 via its N-terminal Cys30–Cys33 shuttle disulfide. However, it is unclear how the two shuttle cysteine residues of Erv1 relay electrons from the Mia40 CPC motif to the Erv1 active-site Cys130–Cys133 disulfide. In the present study, using yeast genetic approaches we showed that both shuttle cysteine residues of Erv1 are required for cell growth. In organelle and in vitro studies confirmed that both shuttle cysteine residues were indeed required for import of MIA pathway substrates and Erv1 enzyme function to oxidize Mia40. Furthermore, our results revealed that the two shuttle cysteine residues of Erv1 are functionally distinct. Although Cys33 is essential for forming the intermediate disulfide Cys33–Cys130′ and transferring electrons to the redox active-site directly, Cys30 plays two important roles: (i) dominantly interacts and receives electrons from the Mia40 CPC motif; and (ii) resolves the Erv1 Cys33–Cys130 intermediate disulfide. Taken together, we conclude that both shuttle cysteine residues are required for Erv1 function, and play complementary, but distinct, roles to ensure rapid turnover of active Erv1. PMID:24625320

The Information Content of Discrete Functions and Their Application in Genetic Data Analysis

DOE PAGES

Sakhanenko, Nikita A.; Kunert-Graf, James; Galas, David J.

2017-10-13

The complex of central problems in data analysis consists of three components: (1) detecting the dependence of variables using quantitative measures, (2) defining the significance of these dependence measures, and (3) inferring the functional relationships among dependent variables. We have argued previously that an information theory approach allows separation of the detection problem from the inference of functional form problem. We approach here the third component of inferring functional forms based on information encoded in the functions. Here, we present here a direct method for classifying the functional forms of discrete functions of three variables represented in data sets. Discretemore » variables are frequently encountered in data analysis, both as the result of inherently categorical variables and from the binning of continuous numerical variables into discrete alphabets of values. The fundamental question of how much information is contained in a given function is answered for these discrete functions, and their surprisingly complex relationships are illustrated. The all-important effect of noise on the inference of function classes is found to be highly heterogeneous and reveals some unexpected patterns. We apply this classification approach to an important area of biological data analysis—that of inference of genetic interactions. Genetic analysis provides a rich source of real and complex biological data analysis problems, and our general methods provide an analytical basis and tools for characterizing genetic problems and for analyzing genetic data. Finally, we illustrate the functional description and the classes of a number of common genetic interaction modes and also show how different modes vary widely in their sensitivity to noise.« less

The Information Content of Discrete Functions and Their Application in Genetic Data Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakhanenko, Nikita A.; Kunert-Graf, James; Galas, David J.

The complex of central problems in data analysis consists of three components: (1) detecting the dependence of variables using quantitative measures, (2) defining the significance of these dependence measures, and (3) inferring the functional relationships among dependent variables. We have argued previously that an information theory approach allows separation of the detection problem from the inference of functional form problem. We approach here the third component of inferring functional forms based on information encoded in the functions. Here, we present here a direct method for classifying the functional forms of discrete functions of three variables represented in data sets. Discretemore » variables are frequently encountered in data analysis, both as the result of inherently categorical variables and from the binning of continuous numerical variables into discrete alphabets of values. The fundamental question of how much information is contained in a given function is answered for these discrete functions, and their surprisingly complex relationships are illustrated. The all-important effect of noise on the inference of function classes is found to be highly heterogeneous and reveals some unexpected patterns. We apply this classification approach to an important area of biological data analysis—that of inference of genetic interactions. Genetic analysis provides a rich source of real and complex biological data analysis problems, and our general methods provide an analytical basis and tools for characterizing genetic problems and for analyzing genetic data. Finally, we illustrate the functional description and the classes of a number of common genetic interaction modes and also show how different modes vary widely in their sensitivity to noise.« less

The Information Content of Discrete Functions and Their Application in Genetic Data Analysis.

PubMed

Sakhanenko, Nikita A; Kunert-Graf, James; Galas, David J

2017-12-01

The complex of central problems in data analysis consists of three components: (1) detecting the dependence of variables using quantitative measures, (2) defining the significance of these dependence measures, and (3) inferring the functional relationships among dependent variables. We have argued previously that an information theory approach allows separation of the detection problem from the inference of functional form problem. We approach here the third component of inferring functional forms based on information encoded in the functions. We present here a direct method for classifying the functional forms of discrete functions of three variables represented in data sets. Discrete variables are frequently encountered in data analysis, both as the result of inherently categorical variables and from the binning of continuous numerical variables into discrete alphabets of values. The fundamental question of how much information is contained in a given function is answered for these discrete functions, and their surprisingly complex relationships are illustrated. The all-important effect of noise on the inference of function classes is found to be highly heterogeneous and reveals some unexpected patterns. We apply this classification approach to an important area of biological data analysis-that of inference of genetic interactions. Genetic analysis provides a rich source of real and complex biological data analysis problems, and our general methods provide an analytical basis and tools for characterizing genetic problems and for analyzing genetic data. We illustrate the functional description and the classes of a number of common genetic interaction modes and also show how different modes vary widely in their sensitivity to noise.

A comparative density functional study on electrical properties of layered penta-graphene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Zhi Gen, E-mail: yuzg@ihpc.a-star.edu.sg; Zhang, Yong-Wei, E-mail: zhangyw@ihpc.a-star.edu.sg

We present a comparative study of the influence of the number of layers, the biaxial strain in the range of −3% to 3%, and the stacking misalignments on the electronic properties of a new 2D carbon allotrope, penta-graphene (PG), based on hybrid-functional method within the density functional theory (DFT). In comparison with local exchange-correlation approximation in the DFT, the hybrid-functional provides an accurate description on the degree of p{sub z} orbitals localization and bandgap. Importantly, the predicted bandgap of few-layer PG has a weak layer dependence. The bandgap of monolayer PG is 3.27 eV, approximately equal to those of GaN andmore » ZnO; and the bandgap of few-layer PG decreases slowly with the number of layers (N) and converge to 2.57 eV when N ≥ 4. Our calculations using HSE06 functional on few-layer PG reveal that bandgap engineering by stacking misalignment can further tune the bandgap down to 1.37 eV. Importantly, there is no direct-to-indirect bandgap transition in PG by varying strain, layer number, and stacking misalignment. Owing to its tunable, robustly direct, and wide bandgap characteristics, few-layer PG is promising for optoelectronic and photovoltaic applications.« less

In cell mutational interference mapping experiment (in cell MIME) identifies the 5' polyadenylation signal as a dual regulator of HIV-1 genomic RNA production and packaging.

PubMed

Smyth, Redmond P; Smith, Maureen R; Jousset, Anne-Caroline; Despons, Laurence; Laumond, Géraldine; Decoville, Thomas; Cattenoz, Pierre; Moog, Christiane; Jossinet, Fabrice; Mougel, Marylène; Paillart, Jean-Christophe; von Kleist, Max; Marquet, Roland

2018-05-18

Non-coding RNA regulatory elements are important for viral replication, making them promising targets for therapeutic intervention. However, regulatory RNA is challenging to detect and characterise using classical structure-function assays. Here, we present in cell Mutational Interference Mapping Experiment (in cell MIME) as a way to define RNA regulatory landscapes at single nucleotide resolution under native conditions. In cell MIME is based on (i) random mutation of an RNA target, (ii) expression of mutated RNA in cells, (iii) physical separation of RNA into functional and non-functional populations, and (iv) high-throughput sequencing to identify mutations affecting function. We used in cell MIME to define RNA elements within the 5' region of the HIV-1 genomic RNA (gRNA) that are important for viral replication in cells. We identified three distinct RNA motifs controlling intracellular gRNA production, and two distinct motifs required for gRNA packaging into virions. Our analysis reveals the 73AAUAAA78 polyadenylation motif within the 5' PolyA domain as a dual regulator of gRNA production and gRNA packaging, and demonstrates that a functional polyadenylation signal is required for viral packaging even though it negatively affects gRNA production.

Microbial ecology of fermentative hydrogen producing bioprocesses: useful insights for driving the ecosystem function.

PubMed

Cabrol, Lea; Marone, Antonella; Tapia-Venegas, Estela; Steyer, Jean-Philippe; Ruiz-Filippi, Gonzalo; Trably, Eric

2017-03-01

One of the most important biotechnological challenges is to develop environment friendly technologies to produce new sources of energy. Microbial production of biohydrogen through dark fermentation, by conversion of residual biomass, is an attractive solution for short-term development of bioH2 producing processes. Efficient biohydrogen production relies on complex mixed communities working in tight interaction. Species composition and functional traits are of crucial importance to maintain the ecosystem service. The analysis of microbial community revealed a wide phylogenetic diversity that contributes in different-and still mostly unclear-ways to hydrogen production. Bridging this gap of knowledge between microbial ecology features and ecosystem functionality is essential to optimize the bioprocess and develop strategies toward a maximization of the efficiency and stability of substrate conversion. The aim of this review is to provide a comprehensive overview of the most up-to-date biodata available and discuss the main microbial community features of biohydrogen engineered ecosystems, with a special emphasis on the crucial role of interactions and the relationships between species composition and ecosystem service. The elucidation of intricate relationships between community structure and ecosystem function would make possible to drive ecosystems toward an improved functionality on the basis of microbial ecology principles. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

In cell mutational interference mapping experiment (in cell MIME) identifies the 5′ polyadenylation signal as a dual regulator of HIV-1 genomic RNA production and packaging

PubMed Central

Smith, Maureen R; Jousset, Anne-Caroline; Despons, Laurence; Laumond, Géraldine; Decoville, Thomas; Cattenoz, Pierre; Moog, Christiane; Jossinet, Fabrice; Mougel, Marylène; Paillart, Jean-Christophe

2018-01-01

Abstract Non-coding RNA regulatory elements are important for viral replication, making them promising targets for therapeutic intervention. However, regulatory RNA is challenging to detect and characterise using classical structure-function assays. Here, we present in cell Mutational Interference Mapping Experiment (in cell MIME) as a way to define RNA regulatory landscapes at single nucleotide resolution under native conditions. In cell MIME is based on (i) random mutation of an RNA target, (ii) expression of mutated RNA in cells, (iii) physical separation of RNA into functional and non-functional populations, and (iv) high-throughput sequencing to identify mutations affecting function. We used in cell MIME to define RNA elements within the 5′ region of the HIV-1 genomic RNA (gRNA) that are important for viral replication in cells. We identified three distinct RNA motifs controlling intracellular gRNA production, and two distinct motifs required for gRNA packaging into virions. Our analysis reveals the 73AAUAAA78 polyadenylation motif within the 5′ PolyA domain as a dual regulator of gRNA production and gRNA packaging, and demonstrates that a functional polyadenylation signal is required for viral packaging even though it negatively affects gRNA production. PMID:29514260

Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

PubMed

Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

2016-09-01

Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate

PubMed Central

Groman, Stephanie M.; James, Alex S.; Seu, Emanuele; Tran, Steven; Clark, Taylor A.; Harpster, Sandra N.; Crawford, Maverick; Burtner, Joanna Lee; Feiler, Karen; Roth, Robert H.; Elsworth, John D.; London, Edythe D.

2014-01-01

For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. PMID:25339755

Sucrose metabolism gene families and their biological functions

PubMed Central

Jiang, Shu-Ye; Chi, Yun-Hua; Wang, Ji-Zhou; Zhou, Jun-Xia; Cheng, Yan-Song; Zhang, Bao-Lan; Ma, Ali; Vanitha, Jeevanandam; Ramachandran, Srinivasan

2015-01-01

Sucrose, as the main product of photosynthesis, plays crucial roles in plant development. Although studies on general metabolism pathway were well documented, less information is available on the genome-wide identification of these genes, their expansion and evolutionary history as well as their biological functions. We focused on four sucrose metabolism related gene families including sucrose synthase, sucrose phosphate synthase, sucrose phosphate phosphatase and UDP-glucose pyrophosphorylase. These gene families exhibited different expansion and evolutionary history as their host genomes experienced differentiated rates of the whole genome duplication, tandem and segmental duplication, or mobile element mediated gene gain and loss. They were evolutionarily conserved under purifying selection among species and expression divergence played important roles for gene survival after expansion. However, we have detected recent positive selection during intra-species divergence. Overexpression of 15 sorghum genes in Arabidopsis revealed their roles in biomass accumulation, flowering time control, seed germination and response to high salinity and sugar stresses. Our studies uncovered the molecular mechanisms of gene expansion and evolution and also provided new insight into the role of positive selection in intra-species divergence. Overexpression data revealed novel biological functions of these genes in flowering time control and seed germination under normal and stress conditions. PMID:26616172

rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System.

PubMed

Ahmed, Seemin Seher; Schattgen, Stefan A; Frakes, Ashley E; Sikoglu, Elif M; Su, Qin; Li, Jia; Hampton, Thomas G; Denninger, Andrew R; Kirschner, Daniel A; Kaspar, Brian; Matalon, Reuben; Gao, Guangping

2016-06-01

Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.

Antennal sensilla of the stonefly Dinocras cephalotes (Plecoptera: Perlidae).

PubMed

Rebora, Manuela; Tierno de Figueroa, José Manuel; Piersanti, Silvana

2016-11-01

Plecoptera, one of the most primitive groups of Neoptera, are important aquatic insects usually employed as bioindicators of high water quality. Notwithstanding the well-developed antennae of the adult, its sensory abilities are so far not well known. The present paper describes at ultrastructural level under scanning and transmission electron microscopy the antennal sensilla of the adult stonefly Dinocras cephalotes (Plecoptera, Perlidae). Adult males and females show a filiform antenna constituted of a scape, a pedicel and a flagellum composed of very numerous segments with no clear sexual dimorphism in the number and distribution of the antennal sensilla. The most represented sensilla are sensilla trichodea, with different length, whose internal structure reveal their mechanosensory function, sensilla chaetica, with an apical pore, with an internal structure revealing a typical gustatory function, porous pegs representing single-walled olfactory sensilla, digitated pegs with hollow cuticular spoke channels representing double-walled olfactory sensilla, pegs in pits for which we hypothesize a thermo-hygrosensory function. The diversity of described sensilla is discussed in relation to known biological aspects of the studied species. This opens new perspectives in the study of the behavior of these aquatic insects during their adult stage. Copyright © 2016 Elsevier Ltd. All rights reserved.

Uptake and Function Studies of Maternal Milk-derived MicroRNAs*

PubMed Central

Title, Alexandra C.; Denzler, Rémy; Stoffel, Markus

2015-01-01

MicroRNAs (miRNAs) are important regulators of cell-autonomous gene expression that influence many biological processes. They are also released from cells and are present in virtually all body fluids, including blood, urine, saliva, sweat, and milk. The functional role of nutritionally obtained extracellular miRNAs is controversial, and irrefutable demonstration of exogenous miRNA uptake by cells and canonical miRNA function is still lacking. Here we show that miRNAs are present at high levels in the milk of lactating mice. To investigate intestinal uptake of miRNAs in newborn mice, we employed genetic models in which newborn miR-375 and miR-200c/141 knockout mice received milk from wild-type foster mothers. Analysis of the intestinal epithelium, blood, liver, and spleen revealed no evidence for miRNA uptake. miR-375 levels in hepatocytes were at the limit of detection and remained orders of magnitude below the threshold for target gene regulation (between 1000 and 10,000 copies/cell). Furthermore, our study revealed rapid degradation of milk miRNAs in intestinal fluid. Together, our results indicate a nutritional rather than gene-regulatory role of miRNAs in the milk of newborn mice. PMID:26240150

Coupled cryoconite ecosystem structure-function relationships are revealed by comparing bacterial communities in alpine and Arctic glaciers.

PubMed

Edwards, Arwyn; Mur, Luis A J; Girdwood, Susan E; Anesio, Alexandre M; Stibal, Marek; Rassner, Sara M E; Hell, Katherina; Pachebat, Justin A; Post, Barbara; Bussell, Jennifer S; Cameron, Simon J S; Griffith, Gareth Wyn; Hodson, Andrew J; Sattler, Birgit

2014-08-01

Cryoconite holes are known as foci of microbial diversity and activity on polar glacier surfaces, but are virtually unexplored microbial habitats in alpine regions. In addition, whether cryoconite community structure reflects ecosystem functionality is poorly understood. Terminal restriction fragment length polymorphism and Fourier transform infrared metabolite fingerprinting of cryoconite from glaciers in Austria, Greenland and Svalbard demonstrated cryoconite bacterial communities are closely correlated with cognate metabolite fingerprints. The influence of bacterial-associated fatty acids and polysaccharides was inferred, underlining the importance of bacterial community structure in the properties of cryoconite. Thus, combined application of T-RFLP and FT-IR metabolite fingerprinting promises high throughput, and hence, rapid assessment of community structure-function relationships. Pyrosequencing revealed Proteobacteria were particularly abundant, with Cyanobacteria likely acting as ecosystem engineers in both alpine and Arctic cryoconite communities. However, despite these generalities, significant differences in bacterial community structures, compositions and metabolomes are found between alpine and Arctic cryoconite habitats, reflecting the impact of local and regional conditions on the challenges of thriving in glacial ecosystems. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Maximal Neighbor Similarity Reveals Real Communities in Networks

PubMed Central

Žalik, Krista Rizman

2015-01-01

An important problem in the analysis of network data is the detection of groups of densely interconnected nodes also called modules or communities. Community structure reveals functions and organizations of networks. Currently used algorithms for community detection in large-scale real-world networks are computationally expensive or require a priori information such as the number or sizes of communities or are not able to give the same resulting partition in multiple runs. In this paper we investigate a simple and fast algorithm that uses the network structure alone and requires neither optimization of pre-defined objective function nor information about number of communities. We propose a bottom up community detection algorithm in which starting from communities consisting of adjacent pairs of nodes and their maximal similar neighbors we find real communities. We show that the overall advantage of the proposed algorithm compared to the other community detection algorithms is its simple nature, low computational cost and its very high accuracy in detection communities of different sizes also in networks with blurred modularity structure consisting of poorly separated communities. All communities identified by the proposed method for facebook network and E-Coli transcriptional regulatory network have strong structural and functional coherence. PMID:26680448

Using the international classification of functioning to examine the impact of trigger finger.

PubMed

Langer, Danit; Maeir, Adina; Michailevich, Michael; Applebaum, Yael; Luria, Shai

2016-12-01

To evaluate the impact of trigger finger (TF) on hand motor function, activity and participation (A&P) and quality of life (QOL), and to evaluate the association between personal factors (age and gender, disease severity) and body functions (dexterity and strength) with A&P and QOL in patients with TF. Sixty-six patients with TF (study group) and 66 healthy volunteers (control group) participated in the study. TF symptoms were graded using the Quinnell classification. A&P was evaluated using the Disabilities of Arm Shoulder and Hand questionnaire and the QOL using the World Health Organization Quality of Life questionnaire. Dexterity was evaluated using the Functional Dexterity Test and the Purdue Pegboard Test; hand strength was evaluated using the Jamar Dynamometer and Pinch Gauge. The comparisons between the study and control groups revealed significant differences in all measures. The study group reported lower perceived QOL, A&P and reduced hand strength and dexterity. Hierarchical regression analyses revealed that (a) the severity of TF contributed significantly to the explained variance of QOL, while demographics and hand functioning did not; (b) demographics, TF severity and hand function all contributed significantly to the explained variance of A&P. The findings of the study point to the importance of addressing the functional implications and QOL of individuals with TF. Implications for Rehabilitation Although trigger finger is considered to be a mild hand pathology, it has a wide-ranging impact on hand functioning, daily activities and quality of life. Clinicians should include assessments of these outcomes in the treatment of individuals with trigger finger. Treatment efficacy should be evaluated with International Classification of Functioning outcomes, and not limited to symptomatology.

Structure-Function Analysis of a Broad Specificity Populus trichocarpa Endo-β-glucanase Reveals an Evolutionary Link between Bacterial Licheninases and Plant XTH Gene Products*

PubMed Central

Eklöf, Jens M.; Shojania, Shaheen; Okon, Mark; McIntosh, Lawrence P.; Brumer, Harry

2013-01-01

The large xyloglucan endotransglycosylase/hydrolase (XTH) gene family continues to be the focus of much attention in studies of plant cell wall morphogenesis due to the unique catalytic functions of the enzymes it encodes. The XTH gene products compose a subfamily of glycoside hydrolase family 16 (GH16), which also comprises a broad range of microbial endoglucanases and endogalactanases, as well as yeast cell wall chitin/β-glucan transglycosylases. Previous whole-family phylogenetic analyses have suggested that the closest relatives to the XTH gene products are the bacterial licheninases (EC 3.2.1.73), which specifically hydrolyze linear mixed linkage β(1→3)/β(1→4)-glucans. In addition to their specificity for the highly branched xyloglucan polysaccharide, XTH gene products are distinguished from the licheninases and other GH16 enzyme subfamilies by significant active site loop alterations and a large C-terminal extension. Given these differences, the molecular evolution of the XTH gene products in GH16 has remained enigmatic. Here, we present the biochemical and structural analysis of a unique, mixed function endoglucanase from black cottonwood (Populus trichocarpa), which reveals a small, newly recognized subfamily of GH16 members intermediate between the bacterial licheninases and plant XTH gene products. We postulate that this clade comprises an important link in the evolution of the large plant XTH gene families from a putative microbial ancestor. As such, this analysis provides new insights into the diversification of GH16 and further unites the apparently disparate members of this important family of proteins. PMID:23572521

Regulatory network analysis of Epstein-Barr virus identifies functional modules and hub genes involved in infectious mononucleosis.

PubMed

Poorebrahim, Mansour; Salarian, Ali; Najafi, Saeideh; Abazari, Mohammad Foad; Aleagha, Maryam Nouri; Dadras, Mohammad Nasr; Jazayeri, Seyed Mohammad; Ataei, Atousa; Poortahmasebi, Vahdat

2017-05-01

Epstein-Barr virus (EBV) is the most common cause of infectious mononucleosis (IM) and establishes lifetime infection associated with a variety of cancers and autoimmune diseases. The aim of this study was to develop an integrative gene regulatory network (GRN) approach and overlying gene expression data to identify the representative subnetworks for IM and EBV latent infection (LI). After identifying differentially expressed genes (DEGs) in both IM and LI gene expression profiles, functional annotations were applied using gene ontology (GO) and BiNGO tools, and construction of GRNs, topological analysis and identification of modules were carried out using several plugins of Cytoscape. In parallel, a human-EBV GRN was generated using the Hu-Vir database for further analyses. Our analysis revealed that the majority of DEGs in both IM and LI were involved in cell-cycle and DNA repair processes. However, these genes showed a significant negative correlation in the IM and LI states. Furthermore, cyclin-dependent kinase 2 (CDK2) - a hub gene with the highest centrality score - appeared to be the key player in cell cycle regulation in IM disease. The most significant functional modules in the IM and LI states were involved in the regulation of the cell cycle and apoptosis, respectively. Human-EBV network analysis revealed several direct targets of EBV proteins during IM disease. Our study provides an important first report on the response to IM/LI EBV infection in humans. An important aspect of our data was the upregulation of genes associated with cell cycle progression and proliferation.

Tryptophan Scanning Reveals Dense Packing of Connexin Transmembrane Domains in Gap Junction Channels Composed of Connexin32.

PubMed

Brennan, Matthew J; Karcz, Jennifer; Vaughn, Nicholas R; Woolwine-Cunningham, Yvonne; DePriest, Adam D; Escalona, Yerko; Perez-Acle, Tomas; Skerrett, I Martha

2015-07-10

Tryptophan was substituted for residues in all four transmembrane domains of connexin32. Function was assayed using dual cell two-electrode voltage clamp after expression in Xenopus oocytes. Tryptophan substitution was poorly tolerated in all domains, with the greatest impact in TM1 and TM4. For instance, in TM1, 15 substitutions were made, six abolished coupling and five others significantly reduced function. Only TM2 and TM3 included a distinct helical face that lacked sensitivity to tryptophan substitution. Results were visualized on a comparative model of Cx32 hemichannel. In this model, a region midway through the membrane appears highly sensitive to tryptophan substitution and includes residues Arg-32, Ile-33, Met-34, and Val-35. In the modeled channel, pore-facing regions of TM1 and TM2 were highly sensitive to tryptophan substitution, whereas the lipid-facing regions of TM3 and TM4 were variably tolerant. Residues facing a putative intracellular water pocket (the IC pocket) were also highly sensitive to tryptophan substitution. Although future studies will be required to separate trafficking-defective mutants from those that alter channel function, a subset of interactions important for voltage gating was identified. Interactions important for voltage gating occurred mainly in the mid-region of the channel and focused on TM1. To determine whether results could be extrapolated to other connexins, TM1 of Cx43 was scanned revealing similar but not identical sensitivity to TM1 of Cx32. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Multiple Legionella pneumophila effector virulence phenotypes revealed through high-throughput analysis of targeted mutant libraries

PubMed Central

Shames, Stephanie R.; Liu, Luying; Havey, James C.; Schofield, Whitman B.; Goodman, Andrew L.; Roy, Craig R.

2017-01-01

Legionella pneumophila is the causative agent of a severe pneumonia called Legionnaires’ disease. A single strain of L. pneumophila encodes a repertoire of over 300 different effector proteins that are delivered into host cells by the Dot/Icm type IV secretion system during infection. The large number of L. pneumophila effectors has been a limiting factor in assessing the importance of individual effectors for virulence. Here, a transposon insertion sequencing technology called INSeq was used to analyze replication of a pool of effector mutants in parallel both in a mouse model of infection and in cultured host cells. Loss-of-function mutations in genes encoding effector proteins resulted in host-specific or broad virulence phenotypes. Screen results were validated for several effector mutants displaying different virulence phenotypes using genetic complementation studies and infection assays. Specifically, loss-of-function mutations in the gene encoding LegC4 resulted in enhanced L. pneumophila in the lungs of infected mice but not within cultured host cells, which indicates LegC4 augments bacterial clearance by the host immune system. The effector proteins RavY and Lpg2505 were important for efficient replication within both mammalian and protozoan hosts. Further analysis of Lpg2505 revealed that this protein functions as a metaeffector that counteracts host cytotoxicity displayed by the effector protein SidI. Thus, this study identified a large cohort of effectors that contribute to L. pneumophila virulence positively or negatively and has demonstrated regulation of effector protein activities by cognate metaeffectors as being critical for host pathogenesis. PMID:29133401

The crystal structure of the Yersinia pestis iron chaperone YiuA reveals a basic triad binding motif for the chelated metal

PubMed Central

2017-01-01

Biological chelating molecules called siderophores are used to sequester iron and maintain its ferric state. Bacterial substrate-binding proteins (SBPs) bind iron–siderophore complexes and deliver these complexes to ATP-binding cassette (ABC) transporters for import into the cytoplasm, where the iron can be transferred from the siderophore to catalytic enzymes. In Yersinia pestis, the causative agent of plague, the Yersinia iron-uptake (Yiu) ABC transporter has been shown to improve iron acquisition under iron-chelated conditions. The Yiu transporter has been proposed to be an iron–siderophore transporter; however, the precise siderophore substrate is unknown. Therefore, the precise role of the Yiu transporter in Y. pestis survival remains uncharacterized. To better understand the function of the Yiu transporter, the crystal structure of YiuA (YPO1310/y2875), an SBP which functions to present the iron–siderophore substrate to the transporter for import into the cytoplasm, was determined. The 2.20 and 1.77 Å resolution X-ray crystal structures reveal a basic triad binding motif at the YiuA canonical substrate-binding site, indicative of a metal-chelate binding site. Structural alignment and computational docking studies support the function of YiuA in binding chelated metal. Additionally, YiuA contains two mobile helices, helix 5 and helix 10, that undergo 2–3 Å shifts across crystal forms and demonstrate structural breathing of the c-clamp architecture. The flexibility in both c-clamp lobes suggest that YiuA substrate transfer resembles the Venus flytrap mechanism that has been proposed for other SBPs. PMID:29095164

Functionally relevant diversity of closely related Nitrospira in activated sludge.

PubMed

Gruber-Dorninger, Christiane; Pester, Michael; Kitzinger, Katharina; Savio, Domenico F; Loy, Alexander; Rattei, Thomas; Wagner, Michael; Daims, Holger

2015-03-01

Nitrospira are chemolithoautotrophic nitrite-oxidizing bacteria that catalyze the second step of nitrification in most oxic habitats and are important for excess nitrogen removal from sewage in wastewater treatment plants (WWTPs). To date, little is known about their diversity and ecological niche partitioning within complex communities. In this study, the fine-scale community structure and function of Nitrospira was analyzed in two full-scale WWTPs as model ecosystems. In Nitrospira-specific 16S rRNA clone libraries retrieved from each plant, closely related phylogenetic clusters (16S rRNA identities between clusters ranged from 95.8% to 99.6%) within Nitrospira lineages I and II were found. Newly designed probes for fluorescence in situ hybridization (FISH) allowed the specific detection of several of these clusters, whose coexistence in the WWTPs was shown for prolonged periods of several years. In situ ecophysiological analyses based on FISH, relative abundance and spatial arrangement quantification, as well as microautoradiography revealed functional differences of these Nitrospira clusters regarding the preferred nitrite concentration, the utilization of formate as substrate and the spatial coaggregation with ammonia-oxidizing bacteria as symbiotic partners. Amplicon pyrosequencing of the nxrB gene, which encodes subunit beta of nitrite oxidoreductase of Nitrospira, revealed in one of the WWTPs as many as 121 species-level nxrB operational taxonomic units with highly uneven relative abundances in the amplicon library. These results show a previously unrecognized high diversity of Nitrospira in engineered systems, which is at least partially linked to niche differentiation and may have important implications for process stability.

Recent Progress in Alzheimer’s Disease Research, Part 2: Genetics and Epidemiology

PubMed Central

Robinson, Morgan; Lee, Brenda Y.; Hane, Francis T.

2017-01-01

This is the second part of a three-part review series reviewing the most important advances in Alzheimer’s disease (AD) research since 2010. This review covers the latest research on genetics and epidemiology. Epidemiological and genetic studies are revealing important insights into the etiology of, and factors that contribute to AD, as well as areas of priority for research into mechanisms and interventions. The widespread adoption of genome wide association studies has provided compelling evidence of the genetic complexity of AD with genes associated with such diverse physiological function as immunity and lipid metabolism being implicated in AD pathogenesis. PMID:28211812

Sequencing of Seven Haloarchaeal Genomes Reveals Patterns of Genomic Flux

PubMed Central

Lynch, Erin A.; Langille, Morgan G. I.; Darling, Aaron; Wilbanks, Elizabeth G.; Haltiner, Caitlin; Shao, Katie S. Y.; Starr, Michael O.; Teiling, Clotilde; Harkins, Timothy T.; Edwards, Robert A.; Eisen, Jonathan A.; Facciotti, Marc T.

2012-01-01

We report the sequencing of seven genomes from two haloarchaeal genera, Haloferax and Haloarcula. Ease of cultivation and the existence of well-developed genetic and biochemical tools for several diverse haloarchaeal species make haloarchaea a model group for the study of archaeal biology. The unique physiological properties of these organisms also make them good candidates for novel enzyme discovery for biotechnological applications. Seven genomes were sequenced to ∼20×coverage and assembled to an average of 50 contigs (range 5 scaffolds - 168 contigs). Comparisons of protein-coding gene compliments revealed large-scale differences in COG functional group enrichment between these genera. Analysis of genes encoding machinery for DNA metabolism reveals genera-specific expansions of the general transcription factor TATA binding protein as well as a history of extensive duplication and horizontal transfer of the proliferating cell nuclear antigen. Insights gained from this study emphasize the importance of haloarchaea for investigation of archaeal biology. PMID:22848480

Stereodynamics in state-resolved scattering at the gas–liquid interface

PubMed Central

Perkins, Bradford G.; Nesbitt, David J.

2008-01-01

Stereodynamics at the gas–liquid interface provides insight into the important physical interactions that directly influence heterogeneous chemistry at the surface and within the bulk liquid. We investigate molecular beam scattering of CO2 from a liquid perfluoropolyether (PFPE) surface in vacuum [incident energy Einc = 10.6(8) kcal/mol, incident angle θinc = 60°] to specifically reveal rotational angular-momentum directions for scattered molecules. Experimentally, internal quantum state populations and MJ distributions are probed by high-resolution polarization-modulated infrared laser spectroscopy. Analysis of J-state populations reveals dual-channel scattering dynamics characterized by a two-temperature Boltzmann distribution for trapping–desorption and impulsive scattering. In addition, molecular dynamics simulations of CO2 + fluorinated self-assembled monolayers have been used to model CO2 + PFPE dynamics. Experimental results and molecular dynamics simulations reveal highly oriented CO2 distributions that preferentially scatter with “top spin” as a strongly increasing function of J state. PMID:18678907

SSD1, which encodes a plant-specific novel protein, controls plant elongation by regulating cell division in rice.

PubMed

Asano, Kenji; Miyao, Akio; Hirochika, Hirohiko; Kitano, Hidemi; Matsuoka, Makoto; Ashikari, Motoyuki

2010-01-01

Plant height is one of the most important traits in crop improvement. Therefore revealing the mechanism of plant elongation and controlling plant height in accordance with breeding object is important. In this study we analyzed a novel dwarf mutant, ssd1, of which phenotype is different from typical GA- or BR-related dwarf phenotype. ssd1 exhibits pleiotropic defects in elongation of various organs such as stems, roots, leaves, and flowers. ssd1 also shows abnormal cell files and shapes, which suggests defects of normal cell division in the mutant. Map-based cloning and complementation test demonstrated that the dwarf phenotype in ssd1 mutant was caused by insertion of retrotransposon in a gene, which encodes plant-specific protein with unknown biochemical function. A BLAST search revealed that SSD1-like genes exist in diverse plant species, including monocots and dicots, but not fern and moss. Our results demonstrate that SSD1 controls plant elongation by controlling cell division in higher plants.

Molecular dynamics simulations of a K+ channel blocker: Tc1 toxin from Tityus cambridgei.

PubMed

Grottesi, Alessandro; Sansom, Mark S P

2003-01-30

Toxins that block voltage-gated potassium (Kv) channels provide a possible template for improved homology models of the Kv pore. In assessing the interactions of Kv channels and their toxins it is important to determine the dynamic flexibility of the toxins. Multiple 10 ns duration molecular dynamics simulations combined with essential dynamics analysis have been used to explore the flexibility of four different Kv channel-blocking toxins. Three toxins (Tc1, AgTx and ChTx) share a common fold. They also share a common pattern of conformational dynamics, as revealed by essential dynamics analysis of the simulation results. This suggests that some aspects of dynamic behaviour are conserved across a single protein fold class. In each of these three toxins, the residue exhibiting minimum flexibility corresponds to a conserved lysine residue that is suggested to interact with the filter domain of the channel. Thus, comparative simulations reveal functionally important conservation of molecular dynamics as well as protein fold across a family of related toxins.

Solid lipid nanoparticles as a vehicle for brain-targeted drug delivery: two new strategies of functionalization with apolipoprotein E

NASA Astrophysics Data System (ADS)

Rute Neves, Ana; Fontes Queiroz, Joana; Weksler, Babette; Romero, Ignacio A.; Couraud, Pierre-Olivier; Reis, Salette

2015-12-01

Nanotechnology can be an important tool to improve the permeability of some drugs for the blood-brain barrier. In this work we created a new system to enter the brain by functionalizing solid lipid nanoparticles with apolipoprotein E, aiming to enhance their binding to low-density lipoprotein receptors on the blood-brain barrier endothelial cells. Solid lipid nanoparticles were successfully functionalized with apolipoprotein E using two distinct strategies that took advantage of the strong interaction between biotin and avidin. Transmission electron microscopy images revealed spherical nanoparticles, and dynamic light scattering gave a Z-average under 200 nm, a polydispersity index below 0.2, and a zeta potential between -10 mV and -15 mV. The functionalization of solid lipid nanoparticles with apolipoprotein E was demonstrated by infrared spectroscopy and fluorimetric assays. In vitro cytotoxic effects were evaluated by MTT and LDH assays in the human cerebral microvascular endothelial cells (hCMEC/D3) cell line, a human blood-brain barrier model, and revealed no toxicity up to 1.5 mg ml-1 over 4 h of incubation. The brain permeability was evaluated in transwell devices with hCMEC/D3 monolayers, and a 1.5-fold increment in barrier transit was verified for functionalized nanoparticles when compared with non-functionalized ones. The results suggested that these novel apolipoprotein E-functionalized nanoparticles resulted in dynamic stable systems capable of being used for an improved and specialized brain delivery of drugs through the blood-brain barrier.

Can You Ride a Bicycle? The Ability to Ride a Bicycle Prevents Reduced Social Function in Older Adults With Mobility Limitation

PubMed Central

Sakurai, Ryota; Kawai, Hisashi; Yoshida, Hideyo; Fukaya, Taro; Suzuki, Hiroyuki; Kim, Hunkyung; Hirano, Hirohiko; Ihara, Kazushige; Obuchi, Shuichi; Fujiwara, Yoshinori

2016-01-01

Background The health benefits of bicycling in older adults with mobility limitation (ML) are unclear. We investigated ML and functional capacity of older cyclists by evaluating their instrumental activities of daily living (IADL), intellectual activity, and social function. Methods On the basis of interviews, 614 community-dwelling older adults (after excluding 63 participants who never cycled) were classified as cyclists with ML, cyclists without ML, non-cyclists with ML (who ceased bicycling due to physical difficulties), or non-cyclists without ML (who ceased bicycling for other reasons). A cyclist was defined as a person who cycled at least a few times per month, and ML was defined as difficulty walking 1 km or climbing stairs without using a handrail. Functional capacity and physical ability were evaluated by standardized tests. Results Regular cycling was documented in 399 participants, and 74 of them (18.5%) had ML; among non-cyclists, 49 had ML, and 166 did not. Logistic regression analysis for evaluating the relationship between bicycling and functional capacity revealed that non-cyclists with ML were more likely to have reduced IADL and social function compared to cyclists with ML. However, logistic regression analysis also revealed that the risk of bicycle-related falls was significantly associated with ML among older cyclists. Conclusions The ability and opportunity to bicycle may prevent reduced IADL and social function in older adults with ML, although older adults with ML have a higher risk of falls during bicycling. It is important to develop a safe environment for bicycling for older adults. PMID:26902165

Natural Selection and Functional Potentials of Human Noncoding Elements Revealed by Analysis of Next Generation Sequencing Data

PubMed Central

Xu, Shuhua

2015-01-01

Noncoding DNA sequences (NCS) have attracted much attention recently due to their functional potentials. Here we attempted to reveal the functional roles of noncoding sequences from the point of view of natural selection that typically indicates the functional potentials of certain genomic elements. We analyzed nearly 37 million single nucleotide polymorphisms (SNPs) of Phase I data of the 1000 Genomes Project. We estimated a series of key parameters of population genetics and molecular evolution to characterize sequence variations of the noncoding genome within and between populations, and identified the natural selection footprints in NCS in worldwide human populations. Our results showed that purifying selection is prevalent and there is substantial constraint of variations in NCS, while positive selectionis more likely to be specific to some particular genomic regions and regional populations. Intriguingly, we observed larger fraction of non-conserved NCS variants with lower derived allele frequency in the genome, indicating possible functional gain of non-conserved NCS. Notably, NCS elements are enriched for potentially functional markers such as eQTLs, TF motif, and DNase I footprints in the genome. More interestingly, some NCS variants associated with diseases such as Alzheimer's disease, Type 1 diabetes, and immune-related bowel disorder (IBD) showed signatures of positive selection, although the majority of NCS variants, reported as risk alleles by genome-wide association studies, showed signatures of negative selection. Our analyses provided compelling evidence of natural selection forces on noncoding sequences in the human genome and advanced our understanding of their functional potentials that play important roles in disease etiology and human evolution. PMID:26053627

Impact of cognitive function on oral perception in independently living older people.

PubMed

Fukutake, Motoyoshi; Ogawa, Taiji; Ikebe, Kazunori; Mihara, Yusuke; Inomata, Chisato; Takeshita, Hajime; Matsuda, Kenichi; Hatta, Kodai; Gondo, Yasuyuki; Masui, Yukie; Inagaki, Hiroki; Arai, Yasumichi; Kamide, Kei; Ishizaki, Tatsuro; Maeda, Yoshinobu

2018-04-10

Oral tactile perception is important for better mastication, appetite, and enjoyment of food. However, previous investigations have not utilized comprehensible variables thought to have negative effect on oral perception, including aging, denture wearing, and cognitive function. The aim of this study was to elucidate the impact of cognitive function on oral perception in independently living older individuals. The study sample was comprised of 987 participants (466 males, 521 females; age 69-71 years). Oral examinations, assessments of cognitive function in preclinical level by Montreal Cognitive Assessment (MoCA)-J, and determination of oral stereognostic ability as an indicator of oral perception were performed. Related variables were selected by univariate analyses; then, multivariate logistic regression model analysis was conducted. Univariate analyses revealed that number of teeth, removable dentures usage, and cognitive function respectively had a significant relationship with stereognostic score. Next, the subjects were classified into good and poor perception groups (lowest 17.4%) according to oral stereognostic ability. Logistic regression analysis revealed that lower cognitive function was significantly associated with poor oral perception (OR = 0.934, p = 0.017) after controlling for other variables. Cognitive decline even in preclinical stage was associated with reduced oral perception after controlling for gender, tooth number and denture use in independent living older people. This study suggested that preclinical level of change in cognitive function affected oral perception. Dental practitioners and caregivers may need to pay attention to reduced oral perception among older people even if they do not have trouble in daily life.

Characterization of the stability and bio-functionality of tethered proteins on bioengineered scaffolds: implications for stem cell biology and tissue repair.

PubMed

Wang, Ting-Yi; Bruggeman, Kiara A F; Sheean, Rebecca K; Turner, Bradley J; Nisbet, David R; Parish, Clare L

2014-05-23

Various engineering applications have been utilized to deliver molecules and compounds in both innate and biological settings. In the context of biological applications, the timely delivery of molecules can be critical for cellular and organ function. As such, previous studies have demonstrated the superiority of long-term protein delivery, by way of protein tethering onto bioengineered scaffolds, compared with conventional delivery of soluble protein in vitro and in vivo. Despite such benefits little knowledge exists regarding the stability, release kinetics, longevity, activation of intracellular pathway, and functionality of these proteins over time. By way of example, here we examined the stability, degradation and functionality of a protein, glial-derived neurotrophic factor (GDNF), which is known to influence neuronal survival, differentiation, and neurite morphogenesis. Enzyme-linked immunosorbent assays (ELISA) revealed that GDNF, covalently tethered onto polycaprolactone (PCL) electrospun nanofibrous scaffolds, remained present on the scaffold surface for 120 days, with no evidence of protein leaching or degradation. The tethered GDNF protein remained functional and capable of activating downstream signaling cascades, as revealed by its capacity to phosphorylate intracellular Erk in a neural cell line. Furthermore, immobilization of GDNF protein promoted cell survival and differentiation in culture at both 3 and 7 days, further validating prolonged functionality of the protein, well beyond the minutes to hours timeframe observed for soluble proteins under the same culture conditions. This study provides important evidence of the stability and functionality kinetics of tethered molecules. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

FRONTO-STRIATAL FUNCTIONAL CONNECTIVITY DURING RESPONSE INHIBITION IN ALCOHOL DEPENDENCE

PubMed Central

Courtney, Kelly E.; Ghahremani, Dara G.; Ray, Lara A.

2013-01-01

Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the µ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing a Stop Signal Task (SST). The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction (PPI) analyses. Analyses revealed greater alcohol dependence severity associated with weaker functional connectivity between the putamen and prefrontal regions (e.g., the anterior insula, anterior cingulate, and medial prefrontal cortex) during response inhibition. Further, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses. PMID:23240858

High-Throughput Cloning and Expression Library Creation for Functional Proteomics

PubMed Central

Festa, Fernanda; Steel, Jason; Bian, Xiaofang; Labaer, Joshua

2013-01-01

The study of protein function usually requires the use of a cloned version of the gene for protein expression and functional assays. This strategy is particular important when the information available regarding function is limited. The functional characterization of the thousands of newly identified proteins revealed by genomics requires faster methods than traditional single gene experiments, creating the need for fast, flexible and reliable cloning systems. These collections of open reading frame (ORF) clones can be coupled with high-throughput proteomics platforms, such as protein microarrays and cell-based assays, to answer biological questions. In this tutorial we provide the background for DNA cloning, discuss the major high-throughput cloning systems (Gateway® Technology, Flexi® Vector Systems, and Creator™ DNA Cloning System) and compare them side-by-side. We also report an example of high-throughput cloning study and its application in functional proteomics. This Tutorial is part of the International Proteomics Tutorial Programme (IPTP12). Details can be found at http://www.proteomicstutorials.org. PMID:23457047

Functional defect in regulatory T cells in myasthenia gravis

PubMed Central

Thiruppathi, Muthusamy; Rowin, Julie; Jiang, Qin Li; Sheng, Jian Rong; Prabhakar, Bellur S.; Meriggioli, Matthew N.

2012-01-01

Forkhead box P3 (FOXP3)+ is a transcription factor necessary for the function of regulatory T cells (Treg cells). Treg cells maintain immune homeostasis and self-tolerance, and play an important role in the prevention of autoimmune disease. Here, we discuss the role of Treg cells in the pathogenesis of myasthenia gravis (MG) and review evidence indicating that a significant defect in Treg cell in vitro suppressive function exists in MG patients, without an alteration in circulating frequency. This functional defect is associated with a reduced expression of key functional molecules such as FOXP3 on isolated Treg cells and appears to be more pronounced in immunosuppression-naive MG patients. In vitro administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced the suppressive function of Treg cells and up-regulated FOXP3 expression. These findings indicate a clinically relevant Treg cell–intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target. PMID:23252899

Uniting functional network topology and oscillations in the fronto-parietal single unit network of behaving primates.

PubMed

Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg

2016-08-15

The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks.

High-throughput cloning and expression library creation for functional proteomics.

PubMed

Festa, Fernanda; Steel, Jason; Bian, Xiaofang; Labaer, Joshua

2013-05-01

The study of protein function usually requires the use of a cloned version of the gene for protein expression and functional assays. This strategy is particularly important when the information available regarding function is limited. The functional characterization of the thousands of newly identified proteins revealed by genomics requires faster methods than traditional single-gene experiments, creating the need for fast, flexible, and reliable cloning systems. These collections of ORF clones can be coupled with high-throughput proteomics platforms, such as protein microarrays and cell-based assays, to answer biological questions. In this tutorial, we provide the background for DNA cloning, discuss the major high-throughput cloning systems (Gateway® Technology, Flexi® Vector Systems, and Creator(TM) DNA Cloning System) and compare them side-by-side. We also report an example of high-throughput cloning study and its application in functional proteomics. This tutorial is part of the International Proteomics Tutorial Programme (IPTP12). © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Correlates of physical activity participation in community-dwelling older adults.

PubMed

Haley, Christy; Andel, Ross

2010-10-01

The authors examined factors related to participation in walking, gardening or yard work, and sports or exercise in 686 community-dwelling adults 60-95 years of age from Wave IV of the population-based Americans' Changing Lives Study. Logistic regression revealed that male gender, being married, and better functional health were associated with greater likelihood of participating in gardening or yard work (p < .05). Male gender, better functional health, and lower body-mass index were independently associated with greater likelihood of walking (p < .05). Increasing age, male gender, higher education, and better functional health were associated with greater likelihood of participating in sports or exercise (p < .05). Subsequent analyses yielded an interaction of functional health by gender in sport or exercise participation (p = .06), suggesting a greater association between functional health and participation in men. Gender and functional health appear to be particularly important for physical activity participation, which may be useful in guiding future research. Attention to different subgroups may be needed to promote participation in specific activities.

Predictors of Posttraumatic Stress Symptoms Among Adolescent and Young Adult Survivors of Childhood Cancer: Importance of Monitoring Survivors' Experiences of Family Functioning.

PubMed

Kamibeppu, Kiyoko; Murayama, Shiho; Ozono, Shuichi; Sakamoto, Naoko; Iwai, Tsuyako; Asami, Keiko; Maeda, Naoko; Inada, Hiroko; Kakee, Naoko; Okamura, Jun; Horibe, Keizo; Ishida, Yasushi

2015-11-01

The purpose of this study was to identify factors associated with posttraumatic stress symptoms (PTSS) among Japanese long-term childhood cancer survivors (CCSs). Subjects comprised 185 adolescent and young adult (AYA) CCSs who completed anonymous self-report questionnaires. Attending physicians also completed an anonymous disease/treatment data sheet. Mean age of survivors was approximately 8 years at diagnosis and 23 years at participation. Multiple regression analysis showed that family functioning, satisfaction with social support, being female, and interactions between family functioning and gender and age at the time of diagnosis were associated with PTSS among survivors. This study revealed family functioning as the most predictive factor of PTSS among AYA CCSs in Japan. Even when the survivor may have unchangeable risk factors, family functioning can potentially moderate the effects on PTSS. Thus, it is crucial for health professionals to carefully monitor and attend to survivors' experiences of family functioning to mitigate PTSS. © The Author(s) 2015.

The angiosperm phloem sieve tube system: a role in mediating traits important to modern agriculture.

PubMed

Ham, Byung-Kook; Lucas, William J

2014-04-01

The plant vascular system serves a vital function by distributing water, nutrients and hormones essential for growth and development to the various organs of the plant. In this review, attention is focused on the role played by the phloem as the conduit for delivery of both photosynthate and information macromolecules, especially from the context of its mediation in traits that are important to modern agriculture. Resource allocation of sugars and amino acids, by the phloem, to specific sink tissues is of importance to crop yield and global food security. Current findings are discussed in the context of a hierarchical control network that operates to integrate resource allocation to competing sinks. The role of plasmodesmata that connect companion cells to neighbouring sieve elements and phloem parenchyma cells is evaluated in terms of their function as valves, connecting the sieve tube pressure manifold system to the various plant tissues. Recent studies have also revealed that plasmodesmata and the phloem sieve tube system function cooperatively to mediate the long-distance delivery of proteins and a diverse array of RNA species. Delivery of these information macromolecules is discussed in terms of their roles in control over the vegetative-to-floral transition, tuberization in potato, stress-related signalling involving miRNAs, and genetic reprogramming through the delivery of 24-nucleotide small RNAs that function in transcriptional gene silencing in recipient sink organs. Finally, we discuss important future research areas that could contribute to developing agricultural crops with engineered performance characteristics for enhance yield potential.

Neural correlates of the LSD experience revealed by multimodal neuroimaging.

PubMed

Carhart-Harris, Robin L; Muthukumaraswamy, Suresh; Roseman, Leor; Kaelen, Mendel; Droog, Wouter; Murphy, Kevin; Tagliazucchi, Enzo; Schenberg, Eduardo E; Nest, Timothy; Orban, Csaba; Leech, Robert; Williams, Luke T; Williams, Tim M; Bolstridge, Mark; Sessa, Ben; McGonigle, John; Sereno, Martin I; Nichols, David; Hellyer, Peter J; Hobden, Peter; Evans, John; Singh, Krish D; Wise, Richard G; Curran, H Valerie; Feilding, Amanda; Nutt, David J

2016-04-26

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

Neural correlates of the LSD experience revealed by multimodal neuroimaging

PubMed Central

Carhart-Harris, Robin L.; Muthukumaraswamy, Suresh; Roseman, Leor; Kaelen, Mendel; Droog, Wouter; Murphy, Kevin; Tagliazucchi, Enzo; Schenberg, Eduardo E.; Nest, Timothy; Orban, Csaba; Leech, Robert; Williams, Luke T.; Williams, Tim M.; Bolstridge, Mark; Sessa, Ben; McGonigle, John; Sereno, Martin I.; Nichols, David; Hobden, Peter; Evans, John; Singh, Krish D.; Wise, Richard G.; Curran, H. Valerie; Feilding, Amanda; Nutt, David J.

2016-01-01

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others. PMID:27071089

Metabolic Control of Tobacco Pollination by Sugars and Invertases1

PubMed Central

Goetz, Marc; Hirsche, Jörg; Bauerfeind, Martin Andreas; González, María-Cruz; Hyun, Tae Kyung; Eom, Seung Hee; Chriqui, Dominique; Engelke, Thomas; Großkinsky, Dominik K.; Roitsch, Thomas

2017-01-01

Pollination in flowering plants is initiated by germination of pollen grains on stigmas followed by fast growth of pollen tubes representing highly energy-consuming processes. The symplastic isolation of pollen grains and tubes requires import of Suc available in the apoplast. We show that the functional coupling of Suc cleavage by invertases and uptake of the released hexoses by monosaccharide transporters are critical for pollination in tobacco (Nicotiana tabacum). Transcript profiling, in situ hybridization, and immunolocalization of extracellular invertases and two monosaccharide transporters in vitro and in vivo support the functional coupling in supplying carbohydrates for pollen germination and tube growth evidenced by spatiotemporally coordinated expression. Detection of vacuolar invertases in maternal tissues by these approaches revealed metabolic cross talk between male and female tissues and supported the requirement for carbohydrate supply in transmitting tissue during pollination. Tissue-specific expression of an invertase inhibitor and addition of the chemical invertase inhibitor miglitol strongly reduced extracellular invertase activity and impaired pollen germination. Measurements of (competitive) uptake of labeled sugars identified two import pathways for exogenously available Suc into the germinating pollen operating in parallel: direct Suc uptake and via the hexoses after cleavage by extracellular invertase. Reduction of extracellular invertase activity in pollen decreases Suc uptake and severely compromises pollen germination. We further demonstrate that Glc as sole carbon source is sufficient for pollen germination, whereas Suc is supporting tube growth, revealing an important regulatory role of both the invertase substrate and products contributing to a potential metabolic and signaling-based multilayer regulation of pollination by carbohydrates. PMID:27923989

Honey Bee Allatostatins Target Galanin/Somatostatin-Like Receptors and Modulate Learning: A Conserved Function?

PubMed Central

Urlacher, Elodie; Soustelle, Laurent; Parmentier, Marie-Laure; Verlinden, Heleen; Gherardi, Marie-Julie; Fourmy, Daniel; Mercer, Alison R.

2016-01-01

Sequencing of the honeybee genome revealed many neuropeptides and putative neuropeptide receptors, yet functional characterization of these peptidic systems is scarce. In this study, we focus on allatostatins, which were first identified as inhibitors of juvenile hormone synthesis, but whose role in the adult honey bee (Apis mellifera) brain remains to be determined. We characterize the bee allatostatin system, represented by two families: allatostatin A (Apime-ASTA) and its receptor (Apime-ASTA-R); and C-type allatostatins (Apime-ASTC and Apime-ASTCC) and their common receptor (Apime-ASTC-R). Apime-ASTA-R and Apime-ASTC-R are the receptors in bees most closely related to vertebrate galanin and somatostatin receptors, respectively. We examine the functional properties of the two honeybee receptors and show that they are transcriptionally expressed in the adult brain, including in brain centers known to be important for learning and memory processes. Thus we investigated the effects of exogenously applied allatostatins on appetitive olfactory learning in the bee. Our results show that allatostatins modulate learning in this insect, and provide important insights into the evolution of somatostatin/allatostatin signaling. PMID:26741132

Esophageal motor disorders: recent advances.

PubMed

Dogan, Ibrahim; Mittal, Ravinder K

2006-07-01

The aim of this article is to highlight literature published during the last year in the context of previous knowledge. A number of novel techniques - high-resolution manometry, esophageal electrical impedance and intra-luminal ultrasound imaging - have improved our understanding of esophageal function in health and disease. Several studies address the function of longitudinal muscle layer of the esophagus in normal subjects and patients with motor disorders of the esophagus. Esophageal electrical impedance recordings reveal abnormal transit in patients with diffuse esophageal spasm, achalasia and patients with normal manometry. Loss of the mammalian Sprouty2 gene leads to enteric neuronal hyperplasia and esophageal achalasia. Several studies showed excellent long-term results of medical and surgical treatment of achalasia of the esophagus. For the first time, mechanisms of gastroesophageal reflux in critically ill mechanically ventilated patients are reported. Novel pharmacologic strategies in the treatment of reflux disease are highlighted. Several novel techniques, perfected during recent years, have improved our understanding of esophageal function and dysfunction. A number of important observations, reviewed here, provide important insight into the pathogenesis of esophageal motor disorders and treatment of gastroesophageal reflux disease.

Hierarchical Feedback Modules and Reaction Hubs in Cell Signaling Networks

PubMed Central

Xu, Jianfeng; Lan, Yueheng

2015-01-01

Despite much effort, identification of modular structures and study of their organizing and functional roles remain a formidable challenge in molecular systems biology, which, however, is essential in reaching a systematic understanding of large-scale cell regulation networks and hence gaining capacity of exerting effective interference to cell activity. Combining graph theoretic methods with available dynamics information, we successfully retrieved multiple feedback modules of three important signaling networks. These feedbacks are structurally arranged in a hierarchical way and dynamically produce layered temporal profiles of output signals. We found that global and local feedbacks act in very different ways and on distinct features of the information flow conveyed by signal transduction but work highly coordinately to implement specific biological functions. The redundancy embodied with multiple signal-relaying channels and feedback controls bestow great robustness and the reaction hubs seated at junctions of different paths announce their paramount importance through exquisite parameter management. The current investigation reveals intriguing general features of the organization of cell signaling networks and their relevance to biological function, which may find interesting applications in analysis, design and control of bio-networks. PMID:25951347

Modelling dynamics in protein crystal structures by ensemble refinement

PubMed Central

Burnley, B Tom; Afonine, Pavel V; Adams, Paul D; Gros, Piet

2012-01-01

Single-structure models derived from X-ray data do not adequately account for the inherent, functionally important dynamics of protein molecules. We generated ensembles of structures by time-averaged refinement, where local molecular vibrations were sampled by molecular-dynamics (MD) simulation whilst global disorder was partitioned into an underlying overall translation–libration–screw (TLS) model. Modeling of 20 protein datasets at 1.1–3.1 Å resolution reduced cross-validated Rfree values by 0.3–4.9%, indicating that ensemble models fit the X-ray data better than single structures. The ensembles revealed that, while most proteins display a well-ordered core, some proteins exhibit a ‘molten core’ likely supporting functionally important dynamics in ligand binding, enzyme activity and protomer assembly. Order–disorder changes in HIV protease indicate a mechanism of entropy compensation for ordering the catalytic residues upon ligand binding by disordering specific core residues. Thus, ensemble refinement extracts dynamical details from the X-ray data that allow a more comprehensive understanding of structure–dynamics–function relationships. DOI: http://dx.doi.org/10.7554/eLife.00311.001 PMID:23251785

Traceless Immobilization of Analytes for High-Throughput Experiments with SAMDI Mass Spectrometry.

PubMed

Helal, Kazi Y; Alamgir, Azmain; Berns, Eric J; Mrksich, Milan

2018-06-21

Label-free assays, and particularly those based on the combination of mass spectroscopy with surface chemistries, enable high-throughput experiments of a broad range of reactions. However, these methods can still require the incorporation of functional groups that allow immobilization of reactants and products to surfaces prior to analysis. In this paper, we report a traceless method for attaching molecules to a self-assembled monolayer for matrix-assisted laser desorption and ionization (SAMDI) mass spectrometry. This method uses monolayers that are functionalized with a 3-trifluoromethyl-3-phenyl-diazirine group that liberates nitrogen when irradiated and gives a carbene that inserts into a wide range of bonds to covalently immobilize molecules. Analysis of the monolayer with SAMDI then reveals peaks for each of the adducts formed from molecules in the sample. This method is applied to characterize a P450 drug metabolizing enzyme and to monitor a Suzuki-Miyaura coupling chemical reaction and is important because modification of the substrates with a functional group would alter their activities. This method will be important for high-throughput experiments in many areas, including reaction discovery and optimization.

Extensive 5.8S nrDNA polymorphism in Mammillaria (Cactaceae) with special reference to the identification of pseudogenic internal transcribed spacer regions.

PubMed

Harpke, Doerte; Peterson, Angela

2008-05-01

The internal transcribed spacer (ITS) region (ITS1, 5.8S rDNA, ITS2) represents the most widely applied nuclear marker in eukaryotic phylogenetics. Although this region has been assumed to evolve in concert, the number of investigations revealing high degrees of intra-individual polymorphism connected with the presence of pseudogenes has risen. The 5.8S rDNA is the most important diagnostic marker for functionality of the ITS region. In Mammillaria, intra-individual 5.8S rDNA polymorphisms of up to 36% and up to nine different types have been found. Twenty-eight of 30 cloned genomic Mammillaria sequences were identified as putative pseudogenes. For the identification of pseudogenic ITS regions, in addition to formal tests based on substitution rates, we attempted to focus on functional features of the 5.8S rDNA (5.8S motif, secondary structure). The importance of functional data for the identification of pseudogenes is outlined and discussed. The identification of pseudogenes is essential, because they may cause erroneous phylogenies and taxonomic problems.

Chemical Ecology of Stingless Bees.

PubMed

Leonhardt, Sara Diana

2017-04-01

Stingless bees (Hymenoptera, Apidae: Meliponini) represent a highly diverse group of social bees confined to the world's tropics and subtropics. They show a striking diversity of structural and behavioral adaptations and are important pollinators of tropical plants. Despite their diversity and functional importance, their ecology, and especially chemical ecology, has received relatively little attention, particularly compared to their relative the honeybee, Apis mellifera. Here, I review various aspects of the chemical ecology of stingless bees, from communication over resource allocation to defense. I list examples in which functions of specific compounds (or compound groups) have been demonstrated by behavioral experiments, and show that many aspects (e.g., queen-worker interactions, host-parasite interactions, neuronal processing etc.) remain little studied. This review further reveals that the vast majority of studies on the chemical ecology of stingless bees have been conducted in the New World, whereas studies on Old World stingless bees are still comparatively rare. Given the diversity of species, behaviors and, apparently, chemical compounds used, I suggest that stingless bees provide an ideal subject for studying how functional context and the need for species specificity may interact to shape pheromone diversification in social insects.

[Structural and functional changes of myocardium in Chernobyl disaster clean-up workers with atrial fibrillation].

PubMed

Khomaziuk, I M; Habulavichene, Zh M; Khomaziuk, V A

2011-01-01

Particularities and clinical importance of the structural and functional changes of myocardium were estimated in Chernobyl disaster clean-up workers with atrial fibrillation (AF). We examined 122 men with AF, which was associated with ischemic heart disease and arterial hypertension. Paroxysmal AF was diagnosed in 42 patients, 80 patients had permanent AE Control group comprised 80 men without AF. Echocardiography and Doppler studies were performed using ultrasound scanner Aloka SSD-630 (Japan). Significant structural and functional changes of the heart were revealed already in paroxysmal AF and became more pronounced in permanent AF. Increased left atrial size, its ratio to left ventricular end diastolic diameter, diastolic dysfunction were important echocardiographic predictors of AF. Heart walls thickening was accompanied by disorders of myocardial relaxation, increase in myocardial mass led to ischemia, and together they promoted overload, dysfunction of atrium and development of AF. Obligatory echocardiographic examination of the Chernobyl disaster clean-up workers with ischemic heart disease and arterial hypertension is necessary for predicting AF early, ordering adequate therapy in proper time and improving prognosis.

Deep brain stimulation mechanisms: beyond the concept of local functional inhibition.

PubMed

Deniau, Jean-Michel; Degos, Bertrand; Bosch, Clémentine; Maurice, Nicolas

2010-10-01

Deep brain electrical stimulation has become a recognized therapy in the treatment of a variety of motor disorders and has potentially promising applications in a wide range of neurological diseases including neuropsychiatry. Behavioural observation that electrical high-frequency stimulation of a given brain area induces an effect similar to a lesion suggested a mechanism of functional inhibition. In vitro and in vivo experiments as well as per operative recordings in patients have revealed a variety of effects involving local changes of neuronal excitability as well as widespread effects throughout the connected network resulting from activation of axons, including antidromic activation. Here we review current data regarding the local and network activity changes induced by high-frequency stimulation of the subthalamic nucleus and discuss this in the context of motor restoration in Parkinson's disease. Stressing the important functional consequences of axonal activation in deep brain stimulation mechanisms, we highlight the importance of developing anatomical knowledge concerning the fibre connections of the putative therapeutic targets. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Effect of Substrate Mechanics on Cardiomyocyte Maturation and Growth

PubMed Central

Tallawi, Marwa; Rai, Ranjana; Boccaccini, Aldo. R.

2015-01-01

Cardiac tissue engineering constructs are a promising therapeutic treatment for myocardial infarction, which is one of the leading causes of death. In order to further advance the development and regeneration of engineered cardiac tissues using biomaterial platforms, it is important to have a complete overview of the effects that substrates have on cardiomyocyte (CM) morphology and function. This article summarizes recent studies that investigate the effect of mechanical cues on the CM differentiation, maturation, and growth. In these studies, CMs derived from embryos, neonates, and mesenchymal stem cells were seeded on different substrates of various elastic modulus. Measuring the contractile function by force production, work output, and calcium handling, it was seen that cell behavior on substrates was optimized when the substrate stiffness mimicked that of the native tissue. The contractile function reflected changes in the sarcomeric protein confirmation and organization that promoted the contractile ability. The analysis of the literature also revealed that, in addition to matrix stiffness, mechanical stimulation, such as stretching the substrate during cell seeding, also played an important role during cell maturation and tissue development. PMID:25148904

Attenuated BMP1 Function Compromises Osteogenesis, Leading to Bone Fragility in Humans and Zebrafish

PubMed Central

Asharani, P.V.; Keupp, Katharina; Semler, Oliver; Wang, Wenshen; Li, Yun; Thiele, Holger; Yigit, Gökhan; Pohl, Esther; Becker, Jutta; Frommolt, Peter; Sonntag, Carmen; Altmüller, Janine; Zimmermann, Katharina; Greenspan, Daniel S.; Akarsu, Nurten A.; Netzer, Christian; Schönau, Eckhard; Wirth, Radu; Hammerschmidt, Matthias; Nürnberg, Peter; Wollnik, Bernd; Carney, Thomas J.

2012-01-01

Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability. PMID:22482805

Long non-coding RNA Loc554202 regulates proliferation and migration in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Yongguo, E-mail: 1138303166@qq.com; Lu, Jianwei, E-mail: jianwei2010077@163.com; Zhou, Jing, E-mail: 2310848@163.com

2014-04-04

Highlights: • First, we have shown that upregulated of the Loc554202 in breast cancer tissues. • Second, we demonstrated the function of Loc554202 in breast cancer cell. • Finally, we demonstrated that LOC554202 knockdown could inhibit tumor growth in vivo. - Abstract: Data derived from massive cloning and traditional sequencing methods have revealed that long non-coding RNAs (lncRNA) play important roles in the development and progression of cancer. Although many studies suggest that the lncRNAs have different cellular functions, many of them are not yet to be identified and characterized for the mechanism of their functions. To address this question,more » we assay the expression level of lncRNAs–Loc554202 in breast cancer tissues and find that Loc554202 is significantly increased compared with normal control, and associated with advanced pathologic stage and tumor size. Moreover, knockdown of Loc554202 decreased breast cancer cell proliferation, induced apoptosis and inhibits migration/invasion in vitro and impeded tumorigenesis in vivo. These data suggest an important role of Loc554202 in breast tumorigenesis.« less

H3.Y discriminates between HIRA and DAXX chaperone complexes and reveals unexpected insights into human DAXX-H3.3-H4 binding and deposition requirements

PubMed Central

Zink, Lisa-Maria; Delbarre, Erwan; Eberl, H. Christian; Keilhauer, Eva C.; Bönisch, Clemens; Pünzeler, Sebastian; Bartkuhn, Marek; Collas, Philippe; Mann, Matthias

2017-01-01

Abstract Histone chaperones prevent promiscuous histone interactions before chromatin assembly. They guarantee faithful deposition of canonical histones and functionally specialized histone variants into chromatin in a spatial- and temporally-restricted manner. Here, we identify the binding partners of the primate-specific and H3.3-related histone variant H3.Y using several quantitative mass spectrometry approaches, and biochemical and cell biological assays. We find the HIRA, but not the DAXX/ATRX, complex to recognize H3.Y, explaining its presence in transcriptionally active euchromatic regions. Accordingly, H3.Y nucleosomes are enriched in the transcription-promoting FACT complex and depleted of repressive post-translational histone modifications. H3.Y mutational gain-of-function screens reveal an unexpected combinatorial amino acid sequence requirement for histone H3.3 interaction with DAXX but not HIRA, and for H3.3 recruitment to PML nuclear bodies. We demonstrate the importance and necessity of specific H3.3 core and C-terminal amino acids in discriminating between distinct chaperone complexes. Further, chromatin immunoprecipitation sequencing experiments reveal that in contrast to euchromatic HIRA-dependent deposition sites, human DAXX/ATRX-dependent regions of histone H3 variant incorporation are enriched in heterochromatic H3K9me3 and simple repeat sequences. These data demonstrate that H3.Y's unique amino acids allow a functional distinction between HIRA and DAXX binding and its consequent deposition into open chromatin. PMID:28334823

RNA folding: structure prediction, folding kinetics and ion electrostatics.

PubMed

Tan, Zhijie; Zhang, Wenbing; Shi, Yazhou; Wang, Fenghua

2015-01-01

Beyond the "traditional" functions such as gene storage, transport and protein synthesis, recent discoveries reveal that RNAs have important "new" biological functions including the RNA silence and gene regulation of riboswitch. Such functions of noncoding RNAs are strongly coupled to the RNA structures and proper structure change, which naturally leads to the RNA folding problem including structure prediction and folding kinetics. Due to the polyanionic nature of RNAs, RNA folding structure, stability and kinetics are strongly coupled to the ion condition of solution. The main focus of this chapter is to review the recent progress in the three major aspects in RNA folding problem: structure prediction, folding kinetics and ion electrostatics. This chapter will introduce both the recent experimental and theoretical progress, while emphasize the theoretical modelling on the three aspects in RNA folding.

Complement-Related Regulates Autophagy in Neighboring Cells.

PubMed

Lin, Lin; Rodrigues, Frederico S L M; Kary, Christina; Contet, Alicia; Logan, Mary; Baxter, Richard H G; Wood, Will; Baehrecke, Eric H

2017-06-29

Autophagy degrades cytoplasmic components and is important for development and human health. Although autophagy is known to be influenced by systemic intercellular signals, the proteins that control autophagy are largely thought to function within individual cells. Here, we report that Drosophila macroglobulin complement-related (Mcr), a complement ortholog, plays an essential role during developmental cell death and inflammation by influencing autophagy in neighboring cells. This function of Mcr involves the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Interestingly, Mcr function in epithelial cells is required for macrophage autophagy and migration to epithelial wounds, a Draper-dependent process. This study reveals, unexpectedly, that complement-related from one cell regulates autophagy in neighboring cells via an ancient immune signaling program. Copyright © 2017 Elsevier Inc. All rights reserved.

A study of structural properties of gene network graphs for mathematical modeling of integrated mosaic gene networks.

PubMed

Petrovskaya, Olga V; Petrovskiy, Evgeny D; Lavrik, Inna N; Ivanisenko, Vladimir A

2017-04-01

Gene network modeling is one of the widely used approaches in systems biology. It allows for the study of complex genetic systems function, including so-called mosaic gene networks, which consist of functionally interacting subnetworks. We conducted a study of a mosaic gene networks modeling method based on integration of models of gene subnetworks by linear control functionals. An automatic modeling of 10,000 synthetic mosaic gene regulatory networks was carried out using computer experiments on gene knockdowns/knockouts. Structural analysis of graphs of generated mosaic gene regulatory networks has revealed that the most important factor for building accurate integrated mathematical models, among those analyzed in the study, is data on expression of genes corresponding to the vertices with high properties of centrality.

Controlling nuclear RNA levels.

PubMed

Schmid, Manfred; Jensen, Torben Heick

2018-05-10

RNA turnover is an integral part of cellular RNA homeostasis and gene expression regulation. Whereas the cytoplasmic control of protein-coding mRNA is often the focus of study, we discuss here the less appreciated role of nuclear RNA decay systems in controlling RNA polymerase II (RNAPII)-derived transcripts. Historically, nuclear RNA degradation was found to be essential for the functionalization of transcripts through their proper maturation. Later, it was discovered to also be an important caretaker of nuclear hygiene by removing aberrant and unwanted transcripts. Recent years have now seen a set of new protein complexes handling a variety of new substrates, revealing functions beyond RNA processing and the decay of non-functional transcripts. This includes an active contribution of nuclear RNA metabolism to the overall cellular control of RNA levels, with mechanistic implications during cellular transitions.

Structural and functional partitioning of bread wheat chromosome 3B.

PubMed

Choulet, Frédéric; Alberti, Adriana; Theil, Sébastien; Glover, Natasha; Barbe, Valérie; Daron, Josquin; Pingault, Lise; Sourdille, Pierre; Couloux, Arnaud; Paux, Etienne; Leroy, Philippe; Mangenot, Sophie; Guilhot, Nicolas; Le Gouis, Jacques; Balfourier, Francois; Alaux, Michael; Jamilloux, Véronique; Poulain, Julie; Durand, Céline; Bellec, Arnaud; Gaspin, Christine; Safar, Jan; Dolezel, Jaroslav; Rogers, Jane; Vandepoele, Klaas; Aury, Jean-Marc; Mayer, Klaus; Berges, Hélène; Quesneville, Hadi; Wincker, Patrick; Feuillet, Catherine

2014-07-18

We produced a reference sequence of the 1-gigabase chromosome 3B of hexaploid bread wheat. By sequencing 8452 bacterial artificial chromosomes in pools, we assembled a sequence of 774 megabases carrying 5326 protein-coding genes, 1938 pseudogenes, and 85% of transposable elements. The distribution of structural and functional features along the chromosome revealed partitioning correlated with meiotic recombination. Comparative analyses indicated high wheat-specific inter- and intrachromosomal gene duplication activities that are potential sources of variability for adaption. In addition to providing a better understanding of the organization, function, and evolution of a large and polyploid genome, the availability of a high-quality sequence anchored to genetic maps will accelerate the identification of genes underlying important agronomic traits. Copyright © 2014, American Association for the Advancement of Science.

Abnormal functional connectivity of hippocampus during episodic memory retrieval processing network in amnestic mild cognitive impairment.

PubMed

Bai, Feng; Zhang, Zhijun; Watson, David R; Yu, Hui; Shi, Yongmei; Yuan, Yonggui; Zang, Yufeng; Zhu, Chaozhe; Qian, Yun

2009-06-01

Functional connectivity magnetic resonance imaging technique has revealed the importance of distributed network structures in higher cognitive processes in the human brain. The hippocampus has a key role in a distributed network supporting memory encoding and retrieval. Hippocampal dysfunction is a recurrent finding in memory disorders of aging such as amnestic mild cognitive impairment (aMCI) in which learning- and memory-related cognitive abilities are the predominant impairment. The functional connectivity method provides a novel approach in our attempts to better understand the changes occurring in this structure in aMCI patients. Functional connectivity analysis was used to examine episodic memory retrieval networks in vivo in twenty 28 aMCI patients and 23 well-matched control subjects, specifically between the hippocampal structures and other brain regions. Compared with control subjects, aMCI patients showed significantly lower hippocampus functional connectivity in a network involving prefrontal lobe, temporal lobe, parietal lobe, and cerebellum, and higher functional connectivity to more diffuse areas of the brain than normal aging control subjects. In addition, those regions associated with increased functional connectivity with the hippocampus demonstrated a significantly negative correlation to episodic memory performance. aMCI patients displayed altered patterns of functional connectivity during memory retrieval. The degree of this disturbance appears to be related to level of impairment of processes involved in memory function. Because aMCI is a putative prodromal syndrome to Alzheimer's disease (AD), these early changes in functional connectivity involving the hippocampus may yield important new data to predict whether a patient will eventually develop AD.

The Biogeographic Pattern of Microbial Functional Genes along an Altitudinal Gradient of the Tibetan Pasture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, Qi; Zhao, Mengxin; Wang, Shiping

As the highest place of the world, the Tibetan plateau is a fragile ecosystem. Given the importance of microbial communities in driving soil nutrient cycling, it is of interest to document the microbial biogeographic pattern here. We adopted a microarray-based tool named GeoChip 4.0 to investigate grassland microbial functional genes along an elevation gradient from 3200 to 3800 m above sea level open to free grazing by local herdsmen and wild animals. Interestingly, microbial functional diversities increase with elevation, so does the relative abundances of genes associated with carbon degradation, nitrogen cycling, methane production, cold shock and oxygen limitation. Themore » range of Shannon diversities (10.27–10.58) showed considerably smaller variation than what was previously observed at ungrazed sites nearby (9.95–10.65), suggesting the important role of livestock grazing on microbial diversities. Closer examination showed that the dissimilarity of microbial community at our study sites increased with elevations, revealing an elevation-decay relationship of microbial functional genes. Both microbial functional diversity and the number of unique genes increased with elevations. Furthermore, we detected a tight linkage of greenhouse gas (CO2) and relative abundances of carbon cycling genes. Our biogeographic study provides insights on microbial functional diversity and soil biogeochemical cycling in Tibetan pastures.« less

Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function.

PubMed

Di, Chao; Xu, Wenying; Su, Zhen; Yuan, Joshua S

2010-10-07

PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms. The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With Arabidopsis as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function. PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out to dissect the PHB gene function. The conserved gene evolution indicated that the study in the model species can be translated to human and mammalian studies.

Localization of the delta opioid receptor and corticotropin-releasing factor in the amygdalar complex: role in anxiety

PubMed Central

Reyes, B. A. S.; Kravets, J. L.; Connelly, K. L.; Unterwald, E. M.; Van Bockstaele, E. J.

2016-01-01

It is well established that central nervous system norepinephrine (NE) and corticotropin releasing factor (CRF) systems are important mediators of behavioral responses to stressors. More recent studies have defined a role for delta opioid receptors (DOPR) in maintaining emotional valence including anxiety. The amygdala plays an important role in processing emotional stimuli, and has been implicated in the development of anxiety disorders. Activation of DOPR or inhibition of CRF in the amygdala reduces baseline and stress-induced anxiety-like responses. It is not known whether CRF- and DOPR-containing amygdalar neurons interact or whether they are regulated by NE afferents. Therefore, the present study sought to better define interactions between the CRF, DOPR and NE systems in the basolateral (BLA) and central nucleus of the amygdala (CeA) of the male rat using anatomical and functional approaches. Irrespective of the amygdalar subregion, dual immunofluorescence microscopy showed that DOPR was present in CRF-containing neurons. Immunoelectron microscopy confirmed that DOPR was localized to both dendritic processes and axon terminals in the BLA and CeA. Semi-quantitative dual immunoelectron microscopy analysis of gold-silver labeling for DOPR and immunoperoxidase labeling for CRF revealed that 55% of the CRF neurons analyzed contained DOPR in the BLA while 67% of the CRF neurons analyzed contained DOPR in the CeA. Furthermore, approximately 41% of DOPR-labeled axon terminals targeted BLA neurons that expressed CRF while 29% of DOPR-labeled axon terminals targeted CeA neurons that expressed CRF. Triple label immunofluorescence microscopy revealed that DOPR and CRF were co-localized in common cellular profiles that were in close proximity to NE-containing fibers in both subregions. These anatomical results indicate significant interactions between DOPR and CRF in this critical limbic region and reveal that NE is poised to regulate these peptidergic systems in the amygdala. Functional studies were performed to determine if activation of DOPR could inhibit the anxiety produced by elevation of NE in the amygdala using the pharmacological stressor yohimbine. Administration of the DOPR agonist, SNC80, significantly attenuated elevated anxiogenic behaviors produced by yohimbine as measured in the rat on the elevated zero maze. Taken together, results from this study demonstrate the convergence of three important systems, NE, CRF, and DOPR, in the amygdala and provide insight into their functional role in modulating stress and anxiety responses. PMID:27376372

Localization of the delta opioid receptor and corticotropin-releasing factor in the amygdalar complex: role in anxiety.

PubMed

Reyes, Beverly A S; Kravets, J L; Connelly, K L; Unterwald, E M; Van Bockstaele, E J

2017-03-01

It is well established that central nervous system norepinephrine (NE) and corticotropin-releasing factor (CRF) systems are important mediators of behavioral responses to stressors. More recent studies have defined a role for delta opioid receptors (DOPR) in maintaining emotional valence including anxiety. The amygdala plays an important role in processing emotional stimuli, and has been implicated in the development of anxiety disorders. Activation of DOPR or inhibition of CRF in the amygdala reduces baseline and stress-induced anxiety-like responses. It is not known whether CRF- and DOPR-containing amygdalar neurons interact or whether they are regulated by NE afferents. Therefore, this study sought to better define interactions between the CRF, DOPR and NE systems in the basolateral (BLA) and central nucleus of the amygdala (CeA) of the male rat using anatomical and functional approaches. Irrespective of the amygdalar subregion, dual immunofluorescence microscopy showed that DOPR was present in CRF-containing neurons. Immunoelectron microscopy confirmed that DOPR was localized to both dendritic processes and axon terminals in the BLA and CeA. Semi-quantitative dual immunoelectron microscopy analysis of gold-silver labeling for DOPR and immunoperoxidase labeling for CRF revealed that 55 % of the CRF neurons analyzed contained DOPR in the BLA while 67 % of the CRF neurons analyzed contained DOPR in the CeA. Furthermore, approximately 41 % of DOPR-labeled axon terminals targeted BLA neurons that expressed CRF while 29 % of DOPR-labeled axon terminals targeted CeA neurons that expressed CRF. Triple label immunofluorescence microscopy revealed that DOPR and CRF were co-localized in common cellular profiles that were in close proximity to NE-containing fibers in both subregions. These anatomical results indicate significant interactions between DOPR and CRF in this critical limbic region and reveal that NE is poised to regulate these peptidergic systems in the amygdala. Functional studies were performed to determine if activation of DOPR could inhibit the anxiety produced by elevation of NE in the amygdala using the pharmacological stressor yohimbine. Administration of the DOPR agonist, SNC80, significantly attenuated elevated anxiogenic behaviors produced by yohimbine as measured in the rat on the elevated zero maze. Taken together, results from this study demonstrate the convergence of three important systems, NE, CRF, and DOPR, in the amygdala and provide insight into their functional role in modulating stress and anxiety responses.

Selection for inpatient rehabilitation after severe stroke: what factors influence rehabilitation assessor decision-making?

PubMed

Hakkennes, Sharon; Hill, Keith D; Brock, Kim; Bernhardt, Julie; Churilov, Leonid

2013-01-01

This study aimed to identify factors that assessors considered important in decision-making regarding suitability for inpatient rehabilitation after acute severe stroke. Multi-site prospective observational cohort study. Consecutive acute, severe stroke patients and their assessors for inpatient rehabilitation. Rehabilitation assessors completed a questionnaire, rating the importance (10 point visual analogue scale) and direction (positive, negative or neutral) of 15 patient related and 2 organisational items potentially affecting their decision regarding patients' acceptance to rehabilitation. Of the 75 patients referred to rehabilitation and included in this study 61 (81.3%) were accepted for inpatient rehabilitation. The items considered to be most important in the decision to accept the patient for rehabilitation were pre-morbid cognition, pre-morbid mobility and pre-morbid communication. For those not accepted the most important items were current mobility, social support and current cognition. Factor analysis revealed 3 underlying factors, interpreted as post-stroke status, pre-morbid status, and social attributes, accounting for 61.8% of the total variance. All were independently associated with acceptance for rehabilitation (p < 0.05). This study highlights the importance of pre-morbid function and social factors in addition to post-stroke function in the decision making process for acceptance to rehabilitation following severe stroke. Future models for selection for rehabilitation should consider inclusion of these factors.

A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation

PubMed Central

Kossel, Albrecht H.; Cambridge, Sidney B.; Wagner, Uta; Bonhoeffer, Tobias

2001-01-01

Neurotrophins have been shown to be involved in functional strengthening of central nervous system synapses. Although their general importance in this process is undisputed, it remains unresolved whether neurotrophins are truly mediators of synaptic strengthening or merely important cofactors. To address this question, we have devised a method to inactivate endogenous brain-derived neurotrophic factor (BDNF) with high time resolution by “caging” a function-blocking mAb against BDNF with a photosensitive protecting compound. Different assays were used to show that this inactivation of the Ab is reversible by UV light. Synaptic potentiation after τ-burst stimulation in the CA1 region of acute hippocampal slices was significantly less when applying the unmodified Ab compared with the caged Ab. Importantly, photoactivation of the caged Ab during the time of induction of synaptic enhancement led to a marked decrease in potentiation. Our experiments therefore strengthen the view that endogenous BDNF has fast effects during induction of synaptic plasticity. The results additionally show that caged Abs can provide a tool for precise spatiotemporal control over endogenous protein levels. PMID:11724927

Research Update: Mechanical properties of metal-organic frameworks - Influence of structure and chemical bonding

NASA Astrophysics Data System (ADS)

Li, Wei; Henke, Sebastian; Cheetham, Anthony K.

2014-12-01

Metal-organic frameworks (MOFs), a young family of functional materials, have been attracting considerable attention from the chemistry, materials science, and physics communities. In the light of their potential applications in industry and technology, the fundamental mechanical properties of MOFs, which are of critical importance for manufacturing, processing, and performance, need to be addressed and understood. It has been widely accepted that the framework topology, which describes the overall connectivity pattern of the MOF building units, is of vital importance for the mechanical properties. However, recent advances in the area of MOF mechanics reveal that chemistry plays a major role as well. From the viewpoint of materials science, a deep understanding of the influence of chemical effects on MOF mechanics is not only highly desirable for the development of novel functional materials with targeted mechanical response, but also for a better understanding of important properties such as structural flexibility and framework breathing. The present work discusses the intrinsic connection between chemical effects and the mechanical behavior of MOFs through a number of prototypical examples.

Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication.

PubMed

Shender, Victoria O; Pavlyukov, Marat S; Ziganshin, Rustam H; Arapidi, Georgij P; Kovalchuk, Sergey I; Anikanov, Nikolay A; Altukhov, Ilya A; Alexeev, Dmitry G; Butenko, Ivan O; Shavarda, Alexey L; Khomyakova, Elena B; Evtushenko, Evgeniy; Ashrafyan, Lev A; Antonova, Irina B; Kuznetcov, Igor N; Gorbachev, Alexey Yu; Shakhparonov, Mikhail I; Govorun, Vadim M

2014-12-01

Ovarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell-cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Structural Basis of Substrate Recognition in Human Nicotinamide N-Methyltransferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Yi; Sartini, Davide; Pozzi, Valentina

2012-05-02

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide, pyridines, and other analogues using S-adenosyl-L-methionine as donor. NNMT plays a significant role in the regulation of metabolic pathways and is expressed at markedly high levels in several kinds of cancers, presenting it as a potential molecular target for cancer therapy. We have determined the crystal structure of human NNMT as a ternary complex bound to both the demethylated donor S-adenosyl-L-homocysteine and the acceptor substrate nicotinamide, to 2.7 {angstrom} resolution. These studies reveal the structural basis for nicotinamide binding and highlight several residues in the active site which may play roles inmore » nicotinamide recognition and NNMT catalysis. The functional importance of these residues was probed by mutagenesis. Of three residues near the nicotinamide's amide group, substitution of S201 and S213 had no effect on enzyme activity while replacement of D197 dramatically decreased activity. Substitutions of Y20, whose side chain hydroxyl interacts with both the nicotinamide aromatic ring and AdoHcy carboxylate, also compromised activity. Enzyme kinetics analysis revealed k{sub cat}/K{sub m} decreases of 2-3 orders of magnitude for the D197A and Y20A mutants, confirming the functional importance of these active site residues. The mutants exhibited substantially increased K{sub m} for both NCA and AdoMet and modestly decreased k{sub cat}. MD simulations revealed long-range conformational effects which provide an explanation for the large increase in K{sub m}(AdoMet) for the D197A mutant, which interacts directly only with nicotinamide in the ternary complex crystal structure.« less

Phenotypic diversity of diploid and haploid Emiliania huxleyi cells and of cells in different growth phases revealed by comparative metabolomics.

PubMed

Mausz, Michaela A; Pohnert, Georg

2015-01-01

In phytoplankton a high species diversity of microalgae co-exists at a given time. But diversity is not only reflected by the species composition. Within these species different life phases as well as different metabolic states can cause additional diversity. One important example is the coccolithophore Emiliania huxleyi. Diploid cells play an important role in marine ecosystems since they can form massively abundant algal blooms but in addition the less abundant haploid life phase of E. huxleyi occurs in lower quantities. Both life phases may fulfill different functions in the plankton. We hypothesize that in addition to the functional diversity caused by this life phase transition the growth stage of cells can also influence the metabolic composition and thus the ecological impact of E. huxleyi. Here we introduce a metabolomic survey in dependence of life phases as well as different growth phases to reveal such changes. The comparative metabolomic approach is based on the extraction of intracellular metabolites from intact microalgae, derivatization and analysis by gas chromatography coupled to mass spectrometry (GC-MS). Automated data processing and statistical analysis using canonical analysis of principal coordinates (CAP) revealed unique metabolic profiles for each life phase. Concerning the correlations of metabolites to growth phases, complex patterns were observed. As for example the saccharide mannitol showed its highest concentration in the exponential phase, whereas fatty acids were correlated to stationary and sterols to declining phase. These results are indicative for specific ecological roles of these stages of E. huxleyi and are discussed in the context of previous physiological and ecological studies. Copyright © 2014 Elsevier GmbH. All rights reserved.

ADSA Foundation Scholar Award: A role for serotonin in lactation physiology-Where do we go from here?

PubMed

Hernandez, L L

2018-04-25

Lactation is a physiological event that is exclusive to mammals. Lactation evolved as a strategy to improve the survival of the young by providing them with the complete nutrition that is required for survival upon birth as well as maternal-offspring bonding. Typically, milk production by the dam matches the demand of the young. The dairy cow is a unique exception in which the discoveries and genetic selection related to lactation physiology have been applied and resulted in a dramatic increase in milk yield of dairy cows. Studies on the role of mammary-derived serotonin and the coordination of various aspects of milk production and maternal metabolism have revealed novel mechanisms by which milk production and maternal metabolism can be improved. Furthermore, the investigation into molecular and cellular mechanisms regulating mammary gland function has revealed the importance of epigenetics on mammary gland function. Understanding mammary gland function at the cellular and physiological levels will be important for improving mammary gland control of maternal metabolism during early lactation. The early lactation period is a critical time for a dairy cow as that is when she is most susceptible to disease and metabolic disorders that can lead to negative effects on her productive capacity and overall health. Our research in the area of serotonin physiology has illustrated the importance of serotonin on the regulation of lactation and maternal homeostasis. Future research in the area of lactation physiology should be targeted at improving maternal health and longevity in the herd through manipulation of the signals the mammary gland sends to coordinate maternal metabolism and synthesize milk. Specifically, we believe that serotonin will play a central role in understanding the communication between the mammary gland and the maternal physiology during lactation. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.

PubMed

Sato, Trey K; Panda, Satchidananda; Miraglia, Loren J; Reyes, Teresa M; Rudic, Radu D; McNamara, Peter; Naik, Kinnery A; FitzGerald, Garret A; Kay, Steve A; Hogenesch, John B

2004-08-19

The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. Here, we describe a genomics-based approach to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN. Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function.

Mitigation of stress: new treatment alternatives.

PubMed

Subhani, Ahmad Rauf; Kamel, Nidal; Mohamad Saad, Mohamad Naufal; Nandagopal, Nanda; Kang, Kenneth; Malik, Aamir Saeed

2018-02-01

Complaints of stress are common in modern life. Psychological stress is a major cause of lifestyle-related issues, contributing to poor quality of life. Chronic stress impedes brain function, causing impairment of many executive functions, including working memory, decision making and attentional control. The current study sought to describe newly developed stress mitigation techniques, and their influence on autonomic and endocrine functions. The literature search revealed that the most frequently studied technique for stress mitigation was biofeedback (BFB). However, evidence suggests that neurofeedback (NFB) and noninvasive brain stimulation (NIBS) could potentially provide appropriate approaches. We found that recent studies of BFB methods have typically used measures of heart rate variability, respiration and skin conductance. In contrast, studies of NFB methods have typically utilized neurocomputation techniques employing electroencephalography, functional magnetic resonance imaging and near infrared spectroscopy. NIBS studies have typically utilized transcranial direct current stimulation methods. Mitigation of stress is a challenging but important research target for improving quality of life.